Search

Acute ischemic stroke (AIS) is a significant brain disease with a high mortality and disability rate. Additional therapies for AIS are urgently needed, and neuroplasticity mechanisms by agents are expected to be neuroprotective for AIS. As a major active component of Salvia miltiorrhiza, salvianolic acid A (SAA) has shown potential for preventing cardiovascular diseases. However, there is no evidence of the long-term effect of SAA on ischemic injury or its mechanism. Therefore, using rats and mice, we systematically investigated the impact of SAA on AIS from the perspective of neuroprotective and neuroplasticity. Here, we report that SAA induces a long-term depression (LTD)-like process in synapses. This antiexcitotoxicity action supports the SAA effect, including alleviating infarction and promoting blood circulation in photothrombosis and middle cerebral artery occlusion (MCAO) models. Furthermore, repeated positron emission tomography/computed tomography (PET/CT) imaging and behavioral assessments two months after AIS induction reveal that acute treatment of SAA promotes recovery from disrupted whole-brain glucose metabolism and impaired spatial memory. These data suggest that acute treatment of SAA is neuroprotective by improving long-term functional outcomes through a synaptic LTD-like process, providing a promising adjunct to current therapies to enable better recovery for AIS.

BK channels can control neuronal function, but their functional relevance in activity-dependent changes of synaptic function remains elusive. Here, we report that repetitive low-frequency stimulation activates BK channels through 12(S)HPETE, an arachidonic acid metabolite, produced downstream of postsynaptic metabotropic glutamate receptors (mGluRs) to trigger long-term depression (LTD) at CA3-CA1 synapses in hippocampal slices from P7-P10 mice. Activation of BK channels is subunit specific, as paxilline but not iberiotoxin blocked mGluR-LTD. Also, 12(S)HPETE does not change the electrophysiological properties of the BK channel when the BKα subunit is expressed alone but increases the channel open probability when the BKα is coexpressed with the β4-subunit. Our findings reveal an interaction between 12(S)HPETE and BK channels to regulate synaptic strength at central synapses and increase our understanding of the mechanisms underlying mGluR-LTD in the neonatal hippocampus that likely contribute to circuit maturation necessary for learning., Competing Interests: Competing interests statement:The authors declare no competing interest.

Long-term potentiation (LTP) and long-term depression (LTD) are widely used to study synaptic plasticity. However, whether proteins regulating LTP and LTD are altered in cognitive disorders and contribute to disease onset remains to be determined. Herein, we induced LTP and LTD in the hippocampal CA3-CA1 Schaffer collateral pathway, respectively, and then performed proteomic analysis of the CA1 region. We identified 20 differentially expressed proteins (DEPs) shared by the LTP and the LTD processes. Among them, we found that HtrA serine peptidase 2 (HTRA2) was mainly expressed in neurons and that HTRA2 levels were increased in both the LTP and the LTD processes in C57BL/6 mice. HTRA2 downregulation impaired synapses and reduced ATP production in cultured primary neurons. Furthermore, adeno-associated virus (AAV)-mediated HTRA2 downregulation in the hippocampus impaired synaptic plasticity and cognitive function in C57BL/6 mice. Moreover, we found that HTRA2 expression decreased in the brains of Alzheimer's disease patients, frontotemporal lobar degeneration with ubiquitin inclusions patients, and tauopathy model mice. Finally, we showed that lentivirus-mediated HTRA2 overexpression in the hippocampus rescued PP2B reduction, alleviated tau hyperphosphorylation, and partially attenuated synaptic plasticity and cognitive deficits in the PS19 tauopathy model mice. Our study not only indicates that HTRA2 in neurons plays an important role in regulating synaptic plasticity under both physiological and pathological conditions, but also provides a novel, electrophysiology-based strategy to identify proteins regulating synaptic plasticity systematically., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The novelty, saliency, and valency of ongoing experiences potently influence the firing rate of the ventral tegmental area (VTA) and the locus coeruleus (LC). Associative experience, in turn, is recorded into memory by means of hippocampal synaptic plasticity that is regulated by noradrenaline sourced from the LC, and dopamine, sourced from both the VTA and LC. Two persistent forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD) support the encoding of different kinds of spatial experience. To what extent the VTA and the LC influence the direction of change of synaptic plasticity and therefore the content of stored experience is not clear. Here, we report that test-pulse activation of Schaffer-collateral-CA1 synapses of freely behaving male rats, in conjunction with VTA stimulation, results in LTP (>24 h), whereas concomitant hippocampal afferent and LC stimulation results in LTD (>24 h). Effects are frequency-dependent (1 to 50 Hz) and competitive: high-frequency (25 Hz), but not low-frequency (5 Hz) optogenetic activation of tyrosine hydroxylase-positive (TH+) neurons in the VTA, results in D1/D5R-dependent LTP, whereas 5 Hz (but not 1, or 25 Hz) activation of TH+ neurons in the LC results in hippocampal LTD that is both D1/D5 and β-AR-dependent. These results suggest that the VTA and LC do not work in synergy, but rather function in a competing fashion to drive different forms of information encoding through synaptic plasticity. Our findings indicate that information transmitted by the VTA and LC is likely to play a decisive role in the shaping of hippocampal information storage and the nature of learned experience., Competing Interests: Competing interests statement:The authors declare no competing interest.

Bone morphogenetic proteins (BMPs), regulators of bone formation, have been implicated in embryogenesis and morphogenesis of various tissues and organs. BMP signaling plays a role in the formation of appropriate synaptic connections and development of normal neural circuits in the brain. However, physiological roles of BMP signaling in postnatal neural functions, including synaptic plasticity, remain largely unknown. Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses in the cerebellum has been suggested one neuronal mechanism underlying cerebellar functions. Here, we explored the contribution of BMP signaling to the induction of mouse cerebellar LTD. We first demonstrated that BMP2 and/or 4 were expressed in GABAergic neurons in mature networks of the cerebellar cortex. mRNA encoding BMP receptor type 1B (Bmpr1b) was expressed in the PC layer. Exogenous application of noggin, a BMP ligand inhibitor, suppressed the induction of cerebellar LTD by conjunctive stimulation, which caused normal LTD under control condition. Furthermore, mice deficient in BMPR1B exhibited attenuation of the extent of LTD induction, whereas they showed normal excitatory synaptic transmission at PF-PC synapses. These results suggest that after postnatal development, BMP signaling activated by BMPR1B, expressed in the PC layer, plays a crucial role in the facilitation of cerebellar LTD, leading to the modulation of cerebellar functions and behaviors., (© 2024 International Society for Neurochemistry.)

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses plays an important role in cerebellum-related motor coordination and learning. LTD is induced by the conjunction of PF stimulation and climbing fiber (CF) stimulation or somatic PC depolarization, while long-term potentiation (LTP) is induced by PF stimulation alone. Therefore, it is considered that different types of stimulation induce different types of synaptic plasticity. However, we found that a small number of conjunctive stimulations (PF + somatic depolarization of PC) induced LTP, but did not induce LTD of a small size. This LTP was not associated with changes in paired-pulse ratio, suggesting postsynaptic origin. Additionally this LTP was dependent on nitric oxide. This LTP was also induced by a smaller number of physiological conjunctive PF and CF stimuli. These results suggested that a larger number or longer period of conjunctive stimulation is required to induce LTD by overcoming LTP. Ca 2+ transients at the PC dendritic region was measured by calcium imaging during LTD-inducing conjunctive stimulation. Peak amplitude of Ca 2+ transients increased gradually during repetitive conjunctive stimulation. Instantaneous peak amplitude was not different between the early phase and late phase, but the average amplitude was larger in the later phase than in the early phase. These results show that LTD overcomes LTP, and increased Ca 2+ integration or a number of stimulations is required for LTD induction., Competing Interests: Declarations. Ethics Approval: All experiments were approved by the Animal Research Committee of the National Center of Neurology and Psychiatry and in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s).)

Spike timing-dependent plasticity (STDP) is a learning rule important for synaptic refinement and for learning and memory during development. While different forms of presynaptic t-LTD have been deeply investigated, little is known about the mechanisms of somatosensory cortex postsynaptic t-LTD. In the present work, we investigated the requirements and mechanisms for induction of developmental spike timing-dependent long-term depression (t-LTD) at L2/3-L2/3 synapses in the juvenile mouse somatosensory cortex. We found that postnatal day (P) 13-21 mice of either sex show t-LTD at L2/3-L2/3 synapses induced by pairing single presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz) that is expressed postsynaptically and requires the activation of ionotropic postsynaptic NMDA-type glutamate receptors containing GluN2B subunits. In addition, it requires postsynaptic Ca 2+ , Ca 2+ release from internal stores, calcineurin, postsynaptic endocannabinoid synthesis, activation of CB 1 receptors, and astrocytic signaling to release the gliotransmitter d-serine to activate postsynaptic NMDARs to induce t-LTD. These results show direct evidence of the mechanism involved in developmental postsynaptic t-LTD at L2/3-L2/3 synapses, revealing a central role of astrocytes and their release of d-serine in its induction., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB 1 R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses., Competing Interests: IM, HC, AR No competing interests declared, (© 2024, Martínez-Gallego, Coatl-Cuaya et al.)

The convergence of conditioned and unconditioned stimuli (CS and US) into the lateral amygdala (LA) serves as a substrate for an adequate fear response in vivo. This well-known Pavlovian paradigm modulates the synaptic plasticity of neurons, as can be proved by the long-term potentiation (LTP) phenomenon in vitro. Although there is an increasing body of evidence for the existence of LTP in the amygdala, only a few studies were able to show a reliable long-term depression (LTD) of excitation in this structure. We have used coronal brain slices and conducted patch-clamp recordings in pyramidal neurons of the lateral amygdala (LA). After obtaining a stable baseline excitatory postsynaptic current (EPSC) response at a holding potential of -70 mV, we employed a paired-pulse paradigm at 1 Hz at the same membrane potential and could observe a reliable LTD. The different durations of stimulation (ranging between 1.5-24 min) were tested first in the same neuron, but the intensity was kept constant. The latter paradigm resulted in a step-wise LTD with a gradually increasing magnitude under these conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). All rights reserved.)

Neuronal excitatory synapses are primarily located on small dendritic protrusions called spines. During synaptic plasticity underlying learning and memory, Ca 2+ influx through postsynaptic NMDA-type glutamate receptors (NMDARs) initiates signaling pathways that coordinate changes in dendritic spine structure and synaptic function. During long-term potentiation (LTP), high levels of NMDAR Ca 2+ influx promote increases in both synaptic strength and dendritic spine size through activation of Ca 2+ -dependent protein kinases. In contrast, during long-term depression (LTD), low levels of NMDAR Ca 2+ influx promote decreased synaptic strength and spine shrinkage and elimination through activation of the Ca 2+ -dependent protein phosphatase calcineurin (CaN), which is anchored at synapses via the scaffold protein A-kinase anchoring protein (AKAP)150. In Alzheimer's disease (AD), the pathological agent amyloid-β (Aβ) may impair learning and memory through biasing NMDAR Ca 2+ signaling pathways toward LTD and spine elimination. By employing AKAP150 knock-in mice of both sexes with a mutation that disrupts CaN anchoring to AKAP150, we revealed that local, postsynaptic AKAP-CaN-LTD signaling was required for Aβ-mediated impairment of NMDAR synaptic Ca 2+ influx, inhibition of LTP, and dendritic spine loss. Additionally, we found that Aβ acutely engages AKAP-CaN signaling through activation of G-protein-coupled metabotropic glutamate receptor 1 (mGluR1) leading to dephosphorylation of NMDAR GluN2B subunits, which decreases Ca 2+ influx to favor LTD over LTP, and cofilin, which promotes F-actin severing to destabilize dendritic spines. These findings reveal a novel interplay between NMDAR and mGluR1 signaling that converges on AKAP-anchored CaN to coordinate dephosphorylation of postsynaptic substrates linked to multiple aspects of Aβ-mediated synaptic dysfunction., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Monocular deprivation (MD) causes an initial decrease in synaptic responses to the deprived eye in juvenile mouse primary visual cortex (V1) through Hebbian long-term depression (LTD). This is followed by a homeostatic increase, which has been attributed either to synaptic scaling or to a slide threshold for Hebbian long-term potentiation (LTP) rather than scaling. We therefore asked in mice of all sexes whether the homeostatic increase during MD requires GluN2B-containing NMDA receptor activity, which is required to slide the plasticity threshold but not for synaptic scaling. Selective GluN2B blockade from 2-6 d after monocular lid suture prevented the homeostatic increase in miniature excitatory postsynaptic current (mEPSC) amplitude in monocular V1 of acute slices and prevented the increase in visually evoked responses in binocular V1 in vivo . The decrease in mEPSC amplitude and visually evoked responses during the first 2 d of MD also required GluN2B activity. Together, these results support the idea that GluN2B-containing NMDA receptors first play a role in LTD immediately following eye closure and then promote homeostasis during prolonged MD by sliding the plasticity threshold in favor of LTP., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The anterior cingulate cortex (ACC) is a key cortical region for pain perception and emotion. Different forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), have been reported in the ACC. Synaptic tagging of LTP plays an important role in hippocampus-related associative memory. In this study, we demonstrate that synaptic tagging of LTD is detected in the ACC of adult male and female mice. This form of tagged LTD requires the activation of metabotropic glutamate receptor subtype 1 (mGluR1). The induction of tagged LTD is time-related with the strongest tagged LTD appearing when the interval between two independent stimuli is 30 min. Inhibitors of mGluR1 blocked the induction of tagged LTD; however, blocking N-methyl-d-aspartate receptors did not affect the induction of tagged LTD. Nimodipine, an inhibitor of L-type voltage-gated calcium channels, also blocked tagged LTD. In an animal model of amputation, we found that tagged LTD was either reduced or completely blocked. Together with our previous report of tagged LTP in the ACC, this study strongly suggests that excitatory synapses in the adult ACC are highly plastic. The biphasic tagging of synaptic transmission provides a new form of heterosynaptic plasticity in the ACC which has functional and pathophysiological significance in phantom pain., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Our studies reveal that SPNs manifest a heterosynaptic, nitric oxide (NO)-dependent form of long-term postsynaptic depression of glutamatergic SPN synapses (NO-LTD) that is preferentially engaged at quiescent synapses. Plasticity is gated by Ca 2+ entry through Ca V 1.3 Ca 2+ channels and phosphodiesterase 1 (PDE1) activation, which blunts intracellular cyclic guanosine monophosphate (cGMP) and NO signaling. Both experimental and simulation studies suggest that this Ca 2+ -dependent regulation of PDE1 activity allows for local regulation of dendritic cGMP signaling. In a mouse model of Parkinson disease (PD), NO-LTD is absent because of impaired interneuronal NO release; re-balancing intrastriatal neuromodulatory signaling restores NO release and NO-LTD. Taken together, these studies provide important insights into the mechanisms governing NO-LTD in SPNs and its role in psychomotor disorders such as PD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion-flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. Here, we identify AETA (Aη), an amyloid-β precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity by competing with the co-agonist and induces an intracellular conformational modification of GluN1 subunits. This favors non-ionotropic NMDAR signaling leading to enhanced LTD and favors spine shrinkage. Endogenously, AETA production is increased by in vivo chemogenetically induced neuronal activity. Genetic deletion of AETA production alters NMDAR transmission and prevents LTD, phenotypes rescued by acute exogenous AETA application. This genetic deletion also impairs contextual fear memory. Our findings demonstrate AETA-dependent NMDAR activation (ADNA), characterizing AETA as a unique type of endogenous NMDAR modulator that exerts bidirectional control over NMDAR signaling and associated information processing., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

NMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g., d-serine) to open the receptor channel, which leads to the influx of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion flux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting results have led to significant controversy. Here, we hypothesized that a major source of contradictory results might be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of long-term depression (LTD) induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker MK801. Conversely, a saturating concentration of d-serine completely inhibited LTD and spine shrinkage induced by glutamate binding in the presence of MK801 or Mg 2+ Using a Förster resonance energy transfer (FRET)-based assay in cultured neurons, we further found that d-serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in which d-serine availability serves to modulate NMDAR signaling and synaptic plasticity even when the NMDAR is blocked by magnesium., Competing Interests: The authors declare no competing financial interests, (Copyright © 2024 the authors.)

Synaptic dysfunction is highly correlated with cognitive impairments in Alzheimer's disease (AD), the most common dementia syndrome in the elderly. Long-term potentiation (LTP) and long-term depression (LTD) are two primary forms of synaptic plasticity with opposite direction of synaptic efficiency change. Both LTD and LTD are considered to mediate the cellular process of learning and memory. Substantial studies demonstrate AD-associated deficiency of both LTP and LTD. Meanwhile, the molecular signaling mechanisms underlying impairment of synaptic plasticity, particularly LTD, are poorly understood. By taking advantage of the novel transgenic mouse models recently developed in our lab, here we aimed to investigate the roles of AMP-activated protein kinase (AMPK), a central molecular senor that plays a critical role in maintaining cellular energy homeostasis, in regulation of LTD phenotypes in AD. We found that brain-specific suppression of the AMPKα1 isoform (but not AMPKα2 isoform) was able to alleviate mGluR-LTD deficits in APP/PS1 AD mouse model. Moreover, suppression of either AMPKα isoform failed to alleviate AD-related NMDAR-dependent LTD deficits. Taken together with our recent studies on roles of AMPK signaling in AD pathophysiology, the data indicate isoform-specific roles of AMPK in mediating AD-associated synaptic and cognitive impairments., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT 1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT 1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT 1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders., (© 2024. The Author(s).)

Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are Hebbian forms of synaptic plasticity that are widely believed to comprise the physiological correlates of associative learning. They comprise a persistent, input-specific increase or decrease, respectively, in synaptic efficacy that, in rodents, can be followed for days and weeks in vivo . Persistent (>24 h) LTP and LTD exhibit distinct frequency-dependencies and molecular profiles in the hippocampal subfields. Moreover, causal and genetic studies in behaving rodents indicate that both LTP and LTD fulfil specific and complementary roles in the acquisition and retention of spatial memory. LTP is likely to be responsible for the generation of a record of spatial experience, which may serve as an associative schema that can be re-used to expedite or facilitate subsequent learning. In contrast, LTD may enable modification and dynamic updating of this representation, such that detailed spatial content information is included and the schema is rendered unique and distinguishable from other similar representations. Together, LTP and LTD engage in a dynamic interplay that supports the generation of complex associative memories that are resistant to generalization. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Synapses form trillions of connections in the brain. Long-term potentiation (LTP) and long-term depression (LTD) are cellular mechanisms vital for learning that modify the strength and structure of synapses. Three-dimensional reconstruction from serial section electron microscopy reveals three distinct pre- to post-synaptic arrangements: strong active zones (AZs) with tightly docked vesicles, weak AZs with loose or non-docked vesicles, and nascent zones (NZs) with a postsynaptic density but no presynaptic vesicles. Importantly, LTP can be temporarily saturated preventing further increases in synaptic strength. At the onset of LTP, vesicles are recruited to NZs, converting them to AZs. During recovery of LTP from saturation (1-4 h), new NZs form, especially on spines where AZs are most enlarged by LTP. Sentinel spines contain smooth endoplasmic reticulum (SER), have the largest synapses and form clusters with smaller spines lacking SER after LTP recovers. We propose a model whereby NZ plasticity provides synapse-specific AZ expansion during LTP and loss of weak AZs that drive synapse shrinkage during LTD. Spine clusters become functionally engaged during LTP or disassembled during LTD. Saturation of LTP or LTD probably acts to protect recently formed memories from ongoing plasticity and may account for the advantage of spaced over massed learning. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Group I metabotropic glutamate receptors (Gp1-mGluRs) exert a host of effects on cellular functions, including enhancement of protein synthesis and the associated facilitation of long-term potentiation (LTP) and induction of long-term depression (LTD). However, the complete cascades of events mediating these events are not fully understood. Gp1-mGluRs trigger α-secretase cleavage of amyloid precursor protein, producing soluble amyloid precursor protein-α (sAPPα), a known regulator of LTP. However, the α-cleavage of APP has not previously been linked to Gp1-mGluR's actions. Using rat hippocampal slices, we found that the α-secretase inhibitor tumour necrosis factor-alpha protease inhibitor-1, which inhibits both disintegrin and metalloprotease 10 (ADAM10) and 17 (ADAM17) activity, blocked or reduced the ability of the Gp1-mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) to stimulate protein synthesis, metaplastically prime future LTP and elicit sub-maximal LTD. In contrast, the specific ADAM10 antagonist GI254023X did not affect the regulation of plasticity, suggesting that ADAM17 but not ADAM10 is involved in mediating these effects of DHPG. However, neither drug affected LTD that was strongly induced by either high-concentration DHPG or paired-pulse synaptic stimulation. Our data suggest that moderate Gp1-mGluR activation triggers α-secretase sheddase activity targeting APP or other membrane-bound proteins as part of a more complex signalling cascade than previously envisioned. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Objectives: Pathological forms of neural activity, such as epileptic seizures, modify the expression pattern of multiple proteins, leading to persistent changes in brain function. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which is critically involved in protein-synthesis-dependent synaptic plasticity underlying learning and memory. In the present study, we have investigated how the expression of ArcKR, a form of Arc in which the ubiquitination sites have been mutated, resulting in slowed Arc degradation, modifies group I metabotropic glutamate receptor-mediated long-term depression (G1-mGluR-LTD) following seizures., Methods: We used a knock-in mice line that express ArcKR and two hyperexcitation models: an in vitro model, where hippocampal slices were exposed to zero Mg 2+ , 6 mM K + ; and an in vivo model, where kainic acid was injected unilaterally into the hippocampus. In both models, field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 region of hippocampal slices in response to Schaffer collateral stimulation and G1-mGluR-LTD was induced chemically with the group 1 mGluR agonist DHPG., Results: In the in vitro model, ArcKR expression enhanced the effects of seizure activity and increased the magnitude of G1-mGluR LTD, an effect that could be blocked with the mGluR5 antagonist MTEP. In the in vivo model, fEPSPs were significantly smaller in slices from ArcKR mice and were less contaminated by population spikes. In this model, the amount of G1-mGluR-LTD was significantly less in epileptic slices from ArcKR mice as compared to wildtype (WT) mice., Significance: We have shown that expression of ArcKR, a form of Arc in which degradation is reduced, significantly modulates the magnitude of G1-mGluR-LTD following epileptic seizures. However, the effect of ArcKR on LTD depends on the epileptic model used, with enhancement of LTD in an in vitro model and a reduction in the kainate mouse model., (© 2024 International League Against Epilepsy.)

Activation of the cAMP pathway is one of the common mechanisms underlying long-term potentiation (LTP). In the Drosophila mushroom body, simultaneous activation of odour-coding Kenyon cells (KCs) and reinforcement-coding dopaminergic neurons activates adenylyl cyclase in KC presynaptic terminals, which is believed to trigger synaptic plasticity underlying olfactory associative learning. However, learning induces long-term depression (LTD) at these synapses, contradicting the universal role of cAMP as a facilitator of transmission. Here, we developed a system to electrophysiologically monitor both short-term and long-term synaptic plasticity at KC output synapses and demonstrated that they are indeed an exception in which activation of the cAMP-protein kinase A pathway induces LTD. Contrary to the prevailing model, our cAMP imaging found no evidence for synergistic action of dopamine and KC activity on cAMP synthesis. Furthermore, we found that forskolin-induced cAMP increase alone was insufficient for plasticity induction; it additionally required simultaneous KC activation to replicate the presynaptic LTD induced by pairing with dopamine. On the other hand, activation of the cGMP pathway paired with KC activation induced slowly developing LTP, proving antagonistic actions of the two second-messenger pathways predicted by behavioural study. Finally, KC subtype-specific interrogation of synapses revealed that different KC subtypes exhibit distinct plasticity duration even among synapses on the same postsynaptic neuron. Thus, our work not only revises the role of cAMP in synaptic plasticity by uncovering the unexpected convergence point of the cAMP pathway and neuronal activity, but also establishes the methods to address physiological mechanisms of synaptic plasticity in this important model. KEY POINTS: Although presynaptic cAMP increase generally facilitates synapses, olfactory associative learning in Drosophila, which depends on dopamine and cAMP signalling genes, induces long-term depression (LTD) at the mushroom body output synapses. By combining electrophysiology, pharmacology and optogenetics, we directly demonstrate that these synapses are an exception where activation of the cAMP-protein kinase A pathway leads to presynaptic LTD. Dopamine- or forskolin-induced cAMP increase alone is not sufficient for LTD induction; neuronal activity, which has been believed to trigger cAMP synthesis in synergy with dopamine input, is required in the downstream pathway of cAMP. In contrast to cAMP, activation of the cGMP pathway paired with neuronal activity induces presynaptic long-term potentiation, which explains behaviourally observed opposing actions of transmitters co-released by dopaminergic neurons. Our work not only revises the role of cAMP in synaptic plasticity, but also provides essential methods to address physiological mechanisms of synaptic plasticity in this important model system., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Training rodents in a particularly difficult olfactory-discrimination (OD) task results in the acquisition of the ability to perform the task well, termed 'rule learning'. In addition to enhanced intrinsic excitability and synaptic excitation in piriform cortex pyramidal neurons, rule learning results in increased synaptic inhibition across the whole cortical network to the point where it precisely maintains the balance between inhibition and excitation. The mechanism underlying such precise inhibitory enhancement remains to be explored. Here, we use brain slices from transgenic mice (VGAT-ChR2-EYFP), enabling optogenetic stimulation of single GABAergic neurons and recordings of unitary synaptic events in pyramidal neurons. Quantal analysis revealed that learning-induced enhanced inhibition is mediated by increased quantal size of the evoked inhibitory events. Next, we examined the plasticity of synaptic inhibition induced by long-lasting, intrinsically evoked spike firing in post-synaptic neurons. Repetitive depolarizing current pulses from depolarized (-70 mV) or hyperpolarized (-90 mV) membrane potentials induced long-term depression (LTD) and long-term potentiation (LTP) of synaptic inhibition, respectively. We found a profound bidirectional increase in the ability to induce both LTD, mediated by L-type calcium channels, and LTP, mediated by R-type calcium channels after rule learning. Blocking the GABA B receptor reversed the effect of intrinsic stimulation at -90 mV from LTP to LTD. We suggest that learning greatly enhances the ability to modify the strength of synaptic inhibition of principal neurons in both directions. Such plasticity of synaptic plasticity allows fine-tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule. KEY POINTS: Olfactory discrimination rule learning results in long-lasting enhancement of synaptic inhibition on piriform cortex pyramidal neurons. Quantal analysis of unitary inhibitory synaptic events, evoked by optogenetic minimal stimulation, revealed that enhanced synaptic inhibition is mediated by increased quantal size. Surprisingly, metaplasticity of synaptic inhibition, induced by intrinsically evoked repetitive spike firing, is increased bidirectionally. The susceptibility to both long-term depression (LTD) and long-term potentiation (LTP) of inhibition is enhanced after learning. LTD of synaptic inhibition is mediated by L-type calcium channels and LTP by R-type calcium channels. LTP is also dependent on activation of GABA B receptors. We suggest that learning-induced changes in the metaplasticity of synaptic inhibition enable the fine-tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Posttranslational modifications regulate the properties and abundance of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that mediate fast excitatory synaptic transmission and synaptic plasticity in the central nervous system. During long-term depression (LTD), protein tyrosine phosphatases (PTPs) dephosphorylate tyrosine residues in the C-terminal tail of AMPA receptor GluA2 subunit, which is essential for GluA2 endocytosis and group I metabotropic glutamate receptor (mGluR)-dependent LTD. However, as a selective downstream effector of mGluRs, the mGluR-dependent PTP responsible for GluA2 tyrosine dephosphorylation remains elusive at Schaffer collateral (SC)-CA1 synapses. In the present study, we find that mGluR5 stimulation activates Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) by increasing phospho-Y542 levels in SHP2. Under steady-state conditions, SHP2 plays a protective role in stabilizing phospho-Y869 of GluA2 by directly interacting with GluA2 phosphorylated at Y869, without affecting GluA2 phospho-Y876 levels. Upon mGluR5 stimulation, SHP2 dephosphorylates GluA2 at Y869 and Y876, resulting in GluA2 endocytosis and mGluR-LTD. Our results establish SHP2 as a downstream effector of mGluR5 and indicate a dual action of SHP2 in regulating GluA2 tyrosine phosphorylation and function. Given the implications of mGluR5 and SHP2 in synaptic pathophysiology, we propose SHP2 as a promising therapeutic target for neurodevelopmental and autism spectrum disorders., Competing Interests: Competing interests statement:The authors declare no competing interest.

Homeostatic regulation of synapses is vital for nervous system function and key to understanding a range of neurological conditions. Synaptic homeostasis is proposed to operate over hours to counteract the destabilizing influence of long-term potentiation (LTP) and long-term depression (LTD). The prevailing view holds that synaptic scaling is a slow first-order process that regulates postsynaptic glutamate receptors and fundamentally differs from LTP or LTD. Surprisingly, we find that the dynamics of scaling induced by neuronal inactivity are not exponential or monotonic, and the mechanism requires calcineurin and CaMKII, molecules dominant in LTD and LTP. Our quantitative model of these enzymes reconstructs the unexpected dynamics of homeostatic scaling and reveals how synapses can efficiently safeguard future capacity for synaptic plasticity. This mechanism of synaptic adaptation supports a broader set of homeostatic changes, including action potential autoregulation, and invites further inquiry into how such a mechanism varies in health and disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Synaptopodin (SP), an actin-associated protein found in telencephalic neurons, affects activity-dependant synaptic plasticity and dynamic changes of dendritic spines. While being required for long-term depression (LTD) mediated by metabotropic glutamate receptor (mGluR-LTD), little is known about its role in other forms of LTD induced by low frequency stimulation (LFS-LTD) or spike-timing dependent plasticity (STDP). Using electrophysiology in ex vivo hippocampal slices from SP-deficient mice (SPKO), we show that absence of SP is associated with a deficit of LTD at Sc-CA1 synapses induced by LFS-LTD and STDP. As LTD is known to require AMPA- receptors internalization and IP3-receptors calcium signaling, we tested by western blotting and immunochemistry if there were changes in their expression which we found to be reduced. While we were not able to induce LTD, long-term potentiation (LTP), albeit diminished in SPKO, can be recovered by using a stronger stimulation protocol. In SPKO we found no differences in NMDAR, which are the primary site of calcium signalling to induce LTP. Our study shows, for the first time, the key role of the requirement of SP to allow induction of activity-dependant LTD at Sc-CA1 synapses., (© 2024. The Author(s).)

Hippocampal afferent inputs, terminating on proximal and distal subfields of the cornus ammonis (CA), enable the functional discrimination of 'what' (item identity) and 'where' (spatial location) elements of a spatial representation. This kind of information is supported by structures such as the retrosplenial cortex (RSC). Spatial content learning promotes the expression of hippocampal synaptic plasticity, particularly long-term depression (LTD). In the CA1 region, this is specifically facilitated by the learning of item-place features of a spatial environment. Gene-tagging, by means of time-locked fluorescence in situ hybridization (FISH) to detect nuclear expression of immediate early genes, can reveal neuronal populations that engage in experience-dependent information encoding. In the current study, using FISH, we examined if learning-facilitated LTD results in subfield-specific information encoding in the hippocampus and RSC. Rats engaged in novel exploration of small items during stimulation of Schaffer collateral-CA1 synapses. This resulted in LTD (> 24 h). FISH, to detect nuclear expression of Homer1a, revealed that the distal-CA1 and proximal-CA3 subcompartments were particularly activated by this event. By contrast, all elements of the proximodistal cornus ammonis-axis showed equal nuclear Homer1a expression following LTD induction solely by means of afferent stimulation. The RSC exhibited stronger nuclear Homer1a expression in response to learning-facilitated LTD, and to novel item-place experience, compared to LTD induced by sole afferent stimulation in CA1. These results show that both the cornus ammonis and RSC engage in differentiated information encoding of item-place learning that is salient enough, in its own right, to drive the expression of hippocampal LTD. These results also reveal a novel role of the RSC in item-place learning., (© 2023. The Author(s).)

Etomidate (ET) is a widely used intravenous imidazole general anesthetic, which depresses the cerebellar neuronal activity by modulating various receptors activity and synaptic transmission. In this study, we investigated the effects of ET on the cerebellar climbing fiber-Purkinje cells (CF-PC) plasticity in vitro in mice using whole-cell recording technique and pharmacological methods. Our results demonstrated that CF tetanic stimulation produced a mGluR1-dependent long-term depression (LTD) of CF-PC excitatory postsynaptic currents (EPSCs), which was enhanced by bath application of ET (10 µM). Blockade of mGluR1 receptor with JNJ16259685, ET triggered the tetanic stimulation to induce a CF-PC LTD accompanied with an increase in paired-pulse ratio (PPR). The ET-triggered CF-PC LTD was abolished by extracellular administration of an N-methyl-(D)-aspartate (NMDA) receptor antagonist, D-APV, as well as by intracellular blockade of NMDA receptors activity with MK801. Furthermore, blocking cannabinoids 1 (CB1) receptor with AM251 or chelating intracellular Ca 2+ with BAPTA, ET failed to trigger the CF-PC LTD. Moreover, the ET-triggered CF-PC LTD was abolished by inhibition of protein kinase A (PKA), but not by inhibition of protein kinase C inhibiter. The present results suggest that ET acts on postsynaptic NMDA receptor resulting in an enhancement of the cerebellar CF-PC LTD through CB1 receptor/PKA cascade in vitro in mice. These results provide new evidence and possible mechanism for ET anesthesia to affect motor learning and motor coordination by regulating cerebellar CF-PC LTD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Synaptic plasticity is one of the putative mechanisms involved in the maturation of the prefrontal cortex (PFC) during postnatal development. Early life stress (ELS) affects the shaping of cortical circuitries through impairment of synaptic plasticity supporting the onset of mood disorders. Growing evidence suggests that dysfunctional postnatal maturation of the prelimbic division (PL) of the PFC might be related to the emergence of depression. The potassium channel TREK-1 has attracted particular interest among many factors that modulate plasticity, concerning synaptic modifications that could underlie mood disorders. Studies have found that ablation of TREK-1 increases the resilience to depression, while rats exposed to ELS exhibit higher TREK-1 levels in the PL. TREK-1 is regulated by multiple intracellular transduction pathways including the ones activated by metabotropic receptors. In the hippocampal neurons, TREK-1 interacts with the serotonergic system, one of the main factors involved in the action of antidepressants. To investigate possible mechanisms related to the antidepressant role of TREK-1, we used brain slice electrophysiology to evaluate the effects of TREK-1 pharmacological blockade on synaptic plasticity at PL circuitry. We extended this investigation to animals subjected to ELS. Our findings suggest that in non-stressed animals, TREK-1 activity is required for the reduction of synaptic responses mediated by the 5HT 1A receptor activation. Furthermore, we demonstrate that TREK-1 blockade promotes activity-dependent long-term depression (LTD) when acting in synergy with 5HT 1A receptor stimulation. On the other hand, in ELS animals, TREK-1 blockade reduces synaptic transmission and facilitates LTD expression. These results indicate that TREK-1 inhibition stimulates synaptic plasticity in the PL and this effect is more pronounced in animals subjected to ELS during postnatal development., Competing Interests: Declaration of Competing Interest All authors of this manuscript (TREK-1 inhibition promotes synaptic plasticity in the prelimbic cortex) declare they have no financial and personal relationships with other people or organizations that could inappropriately influence (bias) this work., (Copyright © 2023. Published by Elsevier Inc.)

Background: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington's disease (HD) induced by 3-nitropropionic acid (3-NP). In the 3-NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin- 3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo., Methods: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways., Results: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT-3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery., Conclusion: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Well known as the center for learning and memory, hippocampus is the crucial brain region to study synaptic plasticity in the context of cellular fundamental mechanisms such as long-term depression (LTD) and long-term potentiation (LTP). However, despite years of extensive research, the key to our LTD queries and their induction mechanisms has not been fully understood. Previously, we reported the induction of late-LTD (L-LTD) in the distally located synapses of apical branch of hippocampal CA1 dendrites using strong low-frequency stimulation (SLFS). In contrast synapses at the proximal site could not express L-LTD. Thus, in the present study, we wanted to investigate whether or not synapses of apical dendritic branch at the proximal location could induce and maintain LTD and its related properties in in vitro rat hippocampal slices. Results indicated that the SLFS in the distal and proximal region triggered the plasticity related proteins (PRP) synthesis in both regions, as evident by the induction and maintenance of L-LTD in the distal region by virtue of synaptic and cross-tagging. In addition, the application of emetine at the time of proximal input stimulation prevented the transition of early-LTD (E-LTD) into L-LTD at the distal region, proving PRP synthesis at the proximal site. Further, it was observed that weak low-frequency stimulation (WLFS) could induce E-LTD in the proximal region along with LTD-specific tag-setting at the synapses. In conclusion, the current study suggests unique findings that the synaptic and cross-tagging mediate L-LTD expression is maintained in the proximal location of hippocampus apical CA1 dendrites., (© 2023 Wiley Periodicals LLC.)

Group I metabotropic glutamate receptors (mGluRI), including mGluR1 and mGluR5 subtypes, modulate essential brain functions by affecting neuronal excitability, intracellular calcium dynamics, protein synthesis, dendritic spine formation, and synaptic transmission and plasticity. Nowadays, it is well appreciated that the mGluRI-dependent long-term depression (LTD) of glutamatergic synaptic transmission (mGluRI-LTD) is a key mechanism by which mGluRI shapes connectivity in various cerebral circuitries, directing complex brain functions and behaviors, and that it is deranged in several neurological and psychiatric illnesses, including neurodevelopmental disorders, neurodegenerative diseases, and psychopathologies. Here, we will provide an updated overview of the physiopathology of mGluRI-LTD, by describing mechanisms of induction and regulation by endogenous mGluRI interactors, as well as functional physiological implications and pathological deviations.

Learning, memory, and cognition are thought to require synaptic plasticity, specifically including hippocampal long-term potentiation and depression (LTP and LTD). LTP versus LTD is induced by high-frequency stimulation versus low-frequency, but stimulating β-adrenergic receptors (βARs) enables LTP induction also by low-frequency stimulation (1 Hz) or theta frequencies (∼5 Hz) that do not cause plasticity by themselves. In contrast to high-frequency stimulation-LTP, such βAR-LTP requires Ca 2+ -flux through L-type voltage-gated Ca 2+ -channels, not N-methyl-D-aspartate-type glutamate receptors. Surprisingly, we found that βAR-LTP still required a nonionotropic scaffolding function of the N-methyl-D-aspartate-type glutamate receptor: the stimulus-induced binding of the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) to its GluN2B subunit that mediates CaMKII movement to excitatory synapses. In hippocampal neurons, β-adrenergic stimulation with isoproterenol (Iso) transformed LTD-type CaMKII movement to LTP-type movement, resulting in CaMKII movement to excitatory instead of inhibitory synapses. Additionally, Iso enabled induction of a major cell-biological feature of LTP in response to LTD stimuli: increased surface expression of GluA1 fused with super-ecliptic pHluorein. Like for βAR-LTP in hippocampal slices, the Iso effects on CaMKII movement and surface expression of GluA1 fused with super-ecliptic pHluorein involved L-type Ca 2+ -channels and specifically required β2-ARs. Taken together, these results indicate that Iso transforms LTD stimuli to LTP signals by switching CaMKII movement and GluN2B binding to LTP mode., Competing Interests: Conflict of interest K. U. B. is co-founder and board member of Neurexis Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Pyramidal cells in hippocampal area CA2 have synaptic properties that are distinct from the other CA subregions. Notably, this includes a lack of typical long-term potentiation of stratum radiatum synapses. CA2 neurons express high levels of several known and potential regulators of metabotropic glutamate receptor (mGluR)-dependent signaling including Striatal-Enriched Tyrosine Phosphatase (STEP) and several Regulator of G-protein Signaling (RGS) proteins, yet the functions of these proteins in regulating mGluR-dependent synaptic plasticity in CA2 are completely unknown. Thus, the aim of this study was to examine mGluR-dependent synaptic depression and to determine whether STEP and the RGS proteins RGS4 and RGS14 are involved. Using whole cell voltage-clamp recordings from mouse pyramidal cells, we found that mGluR agonist-induced long-term depression (mGluR-LTD) is more pronounced in CA2 compared with that observed in CA1. This mGluR-LTD in CA2 was found to be protein synthesis and STEP dependent, suggesting that CA2 mGluR-LTD shares mechanistic processes with those seen in CA1, but in addition, RGS14, but not RGS4, was essential for mGluR-LTD in CA2. In addition, we found that exogenous application of STEP could rescue mGluR-LTD in RGS14 KO slices. Supporting a role for CA2 synaptic plasticity in social cognition, we found that RGS14 KO mice had impaired social recognition memory as assessed in a social discrimination task. These results highlight possible roles for mGluRs, RGS14, and STEP in CA2-dependent behaviors, perhaps by biasing the dominant form of synaptic plasticity away from LTP and toward LTD in CA2., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Thyroid hormones (THs) regulate gene expression by binding to nuclear TH receptors (TRs) in the cell. THs are indispensable for brain development. However, we have little knowledge about how congenital hypothyroidism in neurons affects functions of the central nervous system in adulthood. Here, we report specific TH effects on functional development of the cerebellum by using transgenic mice overexpressing a dominant-negative TR (Mf-1) specifically in cerebellar Purkinje cells (PCs). Adult Mf-1 mice displayed impairments in motor coordination and motor learning. Surprisingly, long-term depression (LTD)-inductive stimulation caused long-term potentiation (LTP) at parallel fiber (PF)-PC synapses in adult Mf-1 mice, although there was no abnormality in morphology or basal properties of PF-PC synapses. The LTP phenotype was turned to LTD in Mf-1 mice when the inductive stimulation was applied in an extracellular high-Ca 2+ condition. Confocal calcium imaging revealed that dendritic Ca 2+ elevation evoked by LTD-inductive stimulation is significantly reduced in Mf-1 PCs but not by PC depolarization only. Single PC messenger RNA quantitative analysis showed reduced expression of SERCA2 and IP 3 receptor type 1 in Mf-1 PCs, which are essential for mGluR1-mediated internal calcium release from endoplasmic reticulum in cerebellar PCs. These abnormal changes were not observed in adult-onset PC-specific TH deficiency mice created by adeno-associated virus vectors. Thus, we propose the importance of TH action during neural development in establishing proper cerebellar function in adulthood, independent of its morphology. The present study gives insight into the cellular and molecular mechanisms underlying congenital hypothyroidism-induced dysfunctions of central nervous system and cerebellum.

Cyanuric acid is one of the most widely used classes of industrial chemicals and is now well known as food adulterant and contaminant in pet food and infant formula. Previously, it was reported that animals prenatally exposed to cyanuric acid showed neurotoxic effects that impaired memory consolidating and suppressed long-term potentiation (LTP) in the hippocampus. However, it is not clear if prenatal exposure to cyanuric acid induces deficits in reversal learning and long-term depression (LTD), which is required for the developmental reorganization of synaptic circuits and updating learned behaviors. Here, pregnant rats were i.p. injected with cyanuric acid (20 mg/kg) during the whole of gestation, and male offspring were selected to examine the levels of hippocampal mGluR1 and mGluR2/3 in young adulthood. The LTD at the Schaffer collateral-CA1 pathway was induced by low-frequency stimulation (LFS) and recorded. Reversal learning and hippocampus-dependent learning strategy were tested in Morris-water maze (MWM) and T-maze tasks, respectively. To further confirm the potential mechanism, selective agonists of mGluR1 and mGluR2/3 and antagonists of mGluR were intra-hippocampal infused before behavioral and neuronal recording. We found the levels of alkaline phosphatase were markedly increased in the maternal placenta and fetal brain following prenatal exposure. The expression of mGluR1 but not mGluR2/3 was significantly decreased and mGluR1-mediated LTD was selectively weakened. Prenatal cyanuric acid impaired reversal learning ability, without changing place learning strategy. The mGluR1 agonist could effectively enhance LFS-induced LTD and mitigate reversal learning deficits. Meanwhile, the reductions in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-mediated spontaneous excitatory postsynaptic currents (sEPSCs) amplitude and frequency of cyanuric acid offspring were simultaneously alleviated by mGluR1 agonist infusions. Therefore, the results indicate the cognitive and synaptic impairments induced by prenatal cyanuric acid exposure are attributed to the disruption of the hippocampal mGluR1 signaling. Our findings provided the first evidence for the deteriorated effects of cyanuric acid on synaptic depression and advanced cognitive performance., Competing Interests: Declaration of Competing Interest There is no conflict of interest for authors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mu opioid receptors (MORs) are expressed in the dorsal striatum, a brain region that mediates goal-directed (via the dorsomedial striatum) and habitual (via the dorsolateral striatum, DLS) behaviours. Our previous work indicates that glutamate transmission is depressed when MORs are activated in the dorsal striatum, inducing MOR-mediated long-term synaptic depression (MOR-LTD) or short-term depression (MOR-STD), depending on the input. In the DLS, MOR-LTD is produced by MORs on anterior insular cortex (AIC) inputs and MOR-STD occurs at thalamic inputs, suggesting input-specific MOR plasticity mechanisms. Here, we evaluated the mechanisms of induction of MOR-LTD and MOR-STD in the DLS using pharmacology and optogenetics combined with patch-clamp electrophysiology. We found that cAMP/PKA signalling and protein synthesis are necessary for MOR-LTD expression, similar to previous studies of cannabinoid-mediated LTD in DLS. MOR-STD does not utilize these same mechanisms. We also demonstrated that cannabinoid-LTD occurs at AIC inputs to DLS. However, while cannabinoid-LTD requires mTOR signalling in DLS, MOR-LTD does not. We characterized the role of presynaptic HCN1 channels in MOR-LTD induction as HCN1 channels expressed in AIC are necessary for MOR-LTD expression in the DLS. These results suggest a mechanism in which MOR activation requires HCN1 to induce MOR-LTD, suggesting a new target for pharmacological modulation of synaptic plasticity, providing new opportunities to develop novel drugs to treat alcohol and opioid use disorders. KEY POINTS: Mu opioid receptor-mediated long-term depression at anterior insular cortex inputs to dorsolateral striatum involves presynaptic cAMP/PKA signalling and protein translation, similar to known mechanisms of cannabinoid long-term depression. Dorsal striatal cannabinoid long-term depression also occurs at anterior insular cortex inputs to the dorsolateral striatum. Dorsal striatal cannabinoid long-term depression requires mTOR signalling, similar to hippocampal cannabinoid long-term depression, but dorsal striatal mu opioid long-term depression does not require mTOR signalling. Mu opioid long-term depression requires presynaptic HCN1 channels at anterior insular cortex inputs to dorsolateral striatum., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

The balance between the actions of protein kinases and phosphatases is crucial for neuronal functions, including synaptic plasticity. Although the phosphorylation and dephosphorylation of neuronal proteins are regulated by synaptic plasticity, no systematic analyses of this have yet been conducted. We performed a phosphoproteomic analysis of hippocampal synaptic plasticity using a nano-Acquity/Synapt LC-MS/MS system. Neuronal proteins were extracted from hippocampal tissues and cultured neurons exposed to long-term potentiation (LTP) or long-term depression (LTD). Filter-aided sample preparation (FASP) was performed to remove residual anionic detergents for complete tryptic digestion. Phosphopeptides were then enriched using TiO 2 chromatography, followed by immunoaffinity chromatography with an anti-phosphotyrosine antibody. Among the 1500 phosphopeptides identified by LC-MS/MS, 374 phosphopeptides were detected simultaneously in both hippocampal tissues and cultured neurons. Semi-quantification counting the number of spectra of each phosphopeptide showed that 42 of 374 phosphopeptides changed significantly depending on synaptic plasticity. In conclusion, a new proteomic method using sequential enrichment of phosphopeptides and semi-quantification enabled the phosphoproteomic analysis of hippocampal synaptic plasticity., Competing Interests: Declaration of competing interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APP swe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) mediates long-term potentiation or depression (LTP or LTD) after distinct stimuli of hippocampal NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD prevails in juvenile mice, but a mechanistically different form of LTD can be readily induced in adults by instead stimulating metabotropic glutamate receptors (mGluRs). However, the role that CaMKII plays in the mGluR-dependent form of LTD is not clear. Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation (pT286), which induces Ca 2+ -independent autonomous kinase activity. In addition, we compared the role of pT286 among three forms of long-term plasticity (NMDAR-dependent LTP and LTD, and mGluR-dependent LTD) using simultaneous live imaging of endogenous CaMKII together with synaptic marker proteins. We determined that after LTP stimuli, pT286 autophosphorylation accelerated CaMKII movement to excitatory synapses. After NMDAR-LTD stimuli, pT286 was strictly required for any movement to inhibitory synapses. Similar to NMDAR-LTD, we found the mGluR-LTD stimuli did not induce CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, we demonstrate that the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Thus, despite its prominent role in LTP, we conclude that CaMKII T286 autophosphorylation is also required for both major forms of hippocampal LTD, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses., Competing Interests: Conflict of interest K. U. B. is cofounder and board member of Neurexis Therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Neurons are highly polarized and functionally compartmentalized cells. Under basal conditions, the biogenesis of autophagic vesicles (AVs) was previously shown to take place in the axon tip. As the sequestration of autophagic cargo occurs during the formation of nascent AVs, this would mean that only axonal proteins can be degraded via macroautophagy/autophagy, unless AV biogenesis can also take place on demand, in other neuronal compartments. Our work shows that indeed, activation of NMDA or group I metabotropic glutamate receptors during long-term synaptic depression (LTD) triggers the biogenesis of AVs locally in dendrites. Under these conditions, nascent dendritic AVs are required for synaptic plasticity, as they sequester postsynaptic proteins, whose removal from the postsynapse is necessary for LTD.

Genetic perturbances in translational regulation result in defects in cerebellar motor learning; however, little is known about the role of translational mechanisms in the regulation of cerebellar plasticity. We show that genetic removal of 4E-BP, a translational suppressor and target of mammalian target of rapamycin complex 1, results in a striking change in cerebellar synaptic plasticity. We find that cerebellar long-term depression (LTD) at parallel fiber-Purkinje cell synapses is converted to long-term potentiation in 4E-BP knockout mice. Biochemical and pharmacological experiments suggest that increased phosphatase activity largely accounts for the defects in LTD. Our results point to a model in which translational regulation through the action of 4E-BP plays a critical role in establishing the appropriate kinase/phosphatase balance required for normal synaptic plasticity in the cerebellum., Competing Interests: Declaration of interests The authors have no financial interests or conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Patterned stimulation of the locus coeruleus (LC, 100 Hz), in conjunction with test-pulse stimulation of hippocampal afferents, results in input-specific long-term depression (LTD) of synaptic plasticity in the hippocampus. Effects are long-lasting and have been described in Schaffer-collateral-CA1 and perforant path-dentate gyrus synapses in behaving rats. To what extent LC-mediated hippocampal LTD (LC-LTD) is frequency-dependent is unclear. Here, we report that LC-LTD can be triggered by LC stimulation with 2 and 5 Hz akin to tonic activity, 10 Hz equivalent to phasic activity, and 100 Hz akin to high-phasic activity in the dentate gyrus (DG) of freely behaving rats. LC-LTD at both 2 and 100 Hz can be significantly prevented by an NMDA receptor antagonist. The LC releases both noradrenaline (NA) and dopamine (DA) from its hippocampal terminals and may also trigger hippocampal DA release by activating the ventral tegmental area (VTA). Unclear is whether both neurotransmitters contribute equally to hippocampal LTD triggered by LC stimulation (LC-LTD). Both DA D1/D5 receptors (D1/D5R) and beta-adrenergic receptors (β-AR) are critically required for hippocampal LTD that is induced by patterned stimulation of hippocampal afferents, or is facilitated by spatial learning. We, therefore, explored to what extent these receptor subtypes mediate frequency-dependent hippocampal LC-LTD. LC-LTD elicited by 2, 5, and 10 Hz stimulation was unaffected by antagonism of β-AR with propranolol, whereas LC-LTD induced by these frequencies was prevented by D1/D5R-antagonism using SCH23390. By contrast, LC-LTD evoked at 100 Hz was prevented by β-AR-antagonism and only mildly affected by D1/D5R-antagonism. Taken together, these findings support that LC-LTD can be triggered by LC activity at a wide range of frequencies. Furthermore, the contribution of D1/D5R and β-AR to hippocampal LTD that is triggered by LC activity is frequency-dependent and suggests that D1/D5R may be involved in LC-mediated hippocampal tonus., (© 2022 The Authors. Hippocampus published by Wiley Periodicals LLC.)

Objective: Depotentiation of homosynaptic plasticity of the primary motor cortex (M1) is impaired in patients with Parkinson's disease (PD) who have developed dyskinesias. In this exploratory study, we tested whether this holds true for heterosynaptic plasticity induced by paired associative stimulation (PAS)., Methods: Dyskinetic (n=11) and Non-dyskinetic (n=11), levodopa-treated PD patients were tested in M1 with PAS 25 ms alone, PAS 25 ms preceded by continuous theta-burst stimulation of the cerebellum (cTBS CB -PAS) as a method to evoke a larger plastic response in M1, and each of these two interventions followed by a depotentiation protocol (cTBS 150 pulses ) to M1., Results: PAS 25 ms and cTBS CB -PAS 25 ms induced long-term potentiation (LTP)-like responses in both groups of PD patients, with cTBS CB significantly boosting the plastic response. Both these LTP-like responses could be depotentiated by cTBS 150 , in both groups of patients., Conclusions: Cerebellar stimulation enhances heterosynaptic plasticity in PD irrespective of dyskinesias. Depotentiation mechanisms of heterosynaptic plasticity are preserved in PD patients, including those with dyskinesias. The lack of depotentiation of LTP-like plasticity as a hallmark of dyskinesia in PD patients is not absolute. The ability to depotentiate LTP-like plasticity may potentially depend on the type of plasticity induced (homosynaptic or heterosynaptic), the circuits involved in these responses and the adequacy of dopaminergic stimulation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Hebbian-type synaptic plasticity which includes long term potentiation (LTP) and long term depression (LTD), is the main cellular mechanism underlying learning and memory. Effective activity and synaptic content of tyrosine phosphatase SHP2 are required for AMPA receptor trafficking during LTP. However, the role of SHP2 in LTD has not been fully elucidated. This study shows that the phosphorylation level of SHP2 at Y542 decreased after LTD induction either in hippocampal cultures or acute CA1 mini slices. This change occurred at least 10 min after LTD induction and was alleviated by administration of NMDA receptor antagonist, APV. Furthermore, the SHP2 mutant (D61G), found in Noonan syndrome patients, prevented the removal of surface AMPA receptors during chemical-induced LTD on cultured hippocampal neurons. The results revealed a molecular basis of regulatory role of SHP2 in long term depression, thus expands our understanding of the SHP2 function in learning and memory., (Copyright © 2022. Published by Elsevier B.V.)

Dendritic spines, actin-rich protrusions forming the postsynaptic sites of excitatory synapses, undergo activity-dependent molecular and structural remodeling. Activation of Group 1 metabotropic glutamate receptors (mGluR1 and mGluR5) by synaptic or pharmacological stimulation, induces LTD, but whether this is accompanied with spine elimination remains unresolved. A subset of telencephalic mushroom spines contains the spine apparatus (SA), an enigmatic organelle composed of stacks of smooth endoplasmic reticulum, whose formation depends on the expression of the actin-bundling protein Synaptopodin. Allocation of Synaptopodin to spines appears governed by cell-intrinsic mechanisms as the relative frequency of spines harboring Synaptopodin is conserved in vivo and in vitro Here we show that expression of Synaptopodin/SA in spines is required for induction of mGluR-LTD at Schaffer collateral-CA1 synapses of male mice. Post-mGluR-LTD, mushroom spines lacking Synaptopodin/SA are selectively lost, whereas spines harboring it are preserved. This process, dependent on activation of mGluR1 but not mGluR5, is conserved in mature mouse neurons and rat neurons of both sexes. Mechanistically, we find that mGluR1 supports physical retention of Synaptopodin within excitatory spine synapses during LTD while triggering lysosome-dependent degradation of the protein residing in dendritic shafts. Together, these results reveal a cellular mechanism, dependent on mGluR1, which enables selective preservation of stronger spines containing Synaptopodin/SA while eliminating weaker ones and potentially countering spurious strengthening by de novo recruitment of Synaptopodin. Overall, our results identify spines with Synaptopodin/SA as the locus of mGluR-LTD and underscore the importance of the molecular microanatomy of spines in synaptic plasticity. SIGNIFICANCE STATEMENT Long-term changes in functional synaptic strength are associated with modification of synaptic connectivity through stabilization or elimination of dendritic spines, the postsynaptic locus of excitatory synapses. How heterogeneous spine microanatomy instructs spine remodeling after long-term synaptic depression (LTD) remains unclear. Metabotropic glutamate receptors mGluR1 and mGluR5 induce a form of LTD critical to circuit function in physiological and disease conditions. Our results identify spines containing the protein Synaptopodin, which enables local assembly of a spine apparatus, as the locus of expression of mGluR-LTD and demonstrate a specific role of mGluR1 in promoting selective loss after mGluR-LTD of mature dendritic spines lacking Synaptopodin/spine apparatus. These findings highlight the fundamental contribution of spine microanatomy in selectively enabling functional and structural plasticity., (Copyright © 2022 the authors.)

Spike-timing-dependent long-term depression (t-LTD) of glutamatergic layer (L)4-L2/3 synapses in developing neocortex requires activation of astrocytes by endocannabinoids (eCBs), which release glutamate onto presynaptic NMDA receptors (preNMDARs). The exact function of preNMDARs in this context is still elusive and strongly debated. To elucidate their function, we show that bath application of the eCB 2-arachidonylglycerol (2-AG) induces a preNMDAR-dependent form of chemically induced LTD (eCB-LTD) in L2/3 pyramidal neurons in the juvenile somatosensory cortex of rats. Presynaptic Ca 2+ imaging from L4 spiny stellate axons revealed that action potential (AP) evoked Ca 2+ transients show a preNMDAR-dependent broadening during eCB-LTD induction. However, blockade of voltage-dependent Ca 2+ channels (VDCCs) did not uncover direct preNMDAR-mediated Ca 2+ transients in the axon. This suggests that astrocyte-mediated glutamate release onto preNMDARs does not result in a direct Ca 2+ influx, but that it instead leads to an indirect interaction with presynaptic VDCCs, boosting axonal Ca 2+ influx. These results reveal one of the main remaining missing pieces in the signaling cascade of t-LTD at developing cortical synapses., Competing Interests: The authors declare no competing financial interests., (Copyright © 2022 Florian B. Neubauer et al.)

The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to speculation that LTD, a fundamental form of synaptic plasticity, also requires autophagy. Here, we show that the induction of LTD via activation of NMDA receptors or metabotropic glutamate receptors initiates autophagy in the postsynaptic dendrites in mice. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPA receptor subunits from the membrane for degradation. During NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. Pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression., (© 2022. The Author(s).)

According to the Bienenstock,Cooper, andMunro's (BCM) model, the level of afferent activity regulates the point of crossover from long-term depression (LTD) to long-term potentiation (LTP) of the active synapses. Although experimental results from the hippocampus and visual cortex have supported the BCM theory, it remains unclear whether previous activity of synapses regulates the output of neuron populations in vivo, as expected from the theory. In the present study, we studied the effects of priming stimulations at different frequencies (LFS, 0.5, 1, 2 and 5 Hz) on the magnitude of LTP at synaptic and somatic levels in the dentate gyrus of hippocampal formation. LTP in the dentate gyrus (DG) of LFS-primed or unprimed hippocampal formation was induced by delivering of tetanic stimulation to the perforant pathway (PP) in anesthetized rats. The field excitatory postsynaptic potential (fEPSP) slope and the population spike (PS) amplitude were evaluated to measure the magnitude of LTP. 1 Hz- and 5 Hz- (not 0.5 Hz and 2 Hz) stimulation of the PP led to an early LTD of fEPSP. The LTP of fEPSP was completely inhibited by previously delivering 0.5 Hz and 2 Hz LFS, but instead converted to LTD by 1 Hz LFS. However, none of the frequencies used was able to inhibit the LTP of PS. These results suggest that temporal dynamics which are critical to determine the direction of synaptic plasticity has no impact on the plasticity of neuronal output. We concluded that it is needed to explain why neuronal output does not behave within the framework of the BCM theory., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Huntington disease (HD) is the most common neurogenetic disorder caused by expansion of the CAG repeat in the HTT gene; nevertheless, the molecular bases of the disease are not fully understood. Non-coding RNAs have demonstrated to be involved in the physiopathology of HD. However, the role of circRNAs has not been investigated. The aim of this study was to identify the circRNAs with differential expression in a murine cell line model of HD and to identify the biological pathways regulated by the differentially expressed circRNAs. CircRNA expression was analyzed through a microarray, which specifically detects circular species of RNA. The expression patterns between a murine cell line expressing mutant Huntingtin and cells expressing wild-type Huntingtin were compared. We predicted the miRNAs with binding sites for the differentially expressed circRNAs and the corresponding target genes for those miRNAs. Using the target genes, we performed a function enrichment analysis. We identified 23 circRNAs differentially expressed, 19 downregulated and four upregulated. Most of the downregulated circRNAs derive from the Rere gene. The dopaminergic synapse, MAPK, and long-term depression pathways were significantly enriched. The three identified pathways have been previously associated with the physiopathology of HD. The understanding of the circRNA-miRNA-mRNA network involved in the molecular mechanisms driving HD can lead us to identify novel biomarkers and potential therapeutic targets. To the best of our knowledge, this is the first study analyzing circRNAs in a model of Huntington disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)