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Synaptic dysfunction is a hallmark of aging and is found in several neurological disorders such as Alzheimer's disease. A common mechanism related to synaptic dysfunction is dysregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which mediate excitatory neurotransmission and synaptic plasticity. Accumulating evidence suggests that tocotrienols, vitamin E molecules that contain an isoprenoid side chain, may promote cognitive improvement in hippocampal-dependent learning tasks. Tocotrienols have also been shown to reduce the secretion of β-amyloid (Aβ) and cholesterol biosynthesis in part by downregulating 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that controls flux of the mevalonate pathway and cholesterol biosynthesis. We hypothesized that tocotrienols might promote cognitive improvement by increasing AMPA receptor-mediated synaptic transmission. Here, we found that δ-tocotrienol increased surface levels of GluA1 but not the GluA2 AMPA receptor subunit in primary hippocampal neurons. Unexpectedly, δ-tocotrienol treatment caused a decrease in the phosphorylation of GluA1 at Serine 845 with no significant changes in GluA1 at Serine 831. Moreover, δ-tocotrienol increased spontaneous excitatory postsynaptic current (sEPSC) amplitude and reduced the secretion of Aβ

Regulation of GABAergic signaling through nicotinic acetylcholine receptor (nAChR) activation is critical for neuronal development. Here, we test the hypothesis that chronic episodic developmental nicotine exposure (eDNE) disrupts GABAergic signaling, leading to dysfunction of hypoglossal motor neurons (XIIMNs), which innervate the tongue muscles. We studied control and eDNE pups at two developmentally vulnerable age ranges: postnatal days (P)1-5 and P10-12. The amplitude and frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs, mIPSCs) at baseline were not altered by eDNE at either age. In contrast, eDNE increased GABA

Orexins are produced in hypothalamic areas and orexin-containing neurons are distributed in widespread areas of the central nervous system. Orexins regulate several physiological functions such as arousal, food intake and autonomic control. The presence of orexin-containing neuron terminals and orexin receptors has been confirmed in the nucleus tractus solitarius (NTS), which receives primary afferent fibers from peripheral organs including baroreceptors. However, the neuronal effects of orexin-1 receptor (OX

The statistics of vesicle release determine how synapses transfer information, but the classical Poisson model of independent release does not always hold at the first stages of vision and hearing. There, ribbon synapses also encode sensory signals as events comprising two or more vesicles released simultaneously. The implications of such coordinated multivesicular release (MVR) for spike generation are not known. Here we investigate how MVR alters the transmission of sensory information compared with Poisson synapses using a pure rate-code. We used leaky integrate-and-fire models incorporating the statistics of release measured experimentally from glutamatergic synapses of retinal bipolar cells in zebrafish (both sexes) and compared these with models assuming Poisson inputs constrained to operate at the same average rates. We find that MVR can increase the number of spikes generated per vesicle while reducing interspike intervals and latency to first spike. The combined effect was to increase the efficiency of information transfer (bits per vesicle) over a range of conditions mimicking target neurons of different size. MVR was most advantageous in neurons with short time constants and reliable synaptic inputs, when less convergence was required to trigger spikes. In the special case of a single input driving a neuron, as occurs in the auditory system of mammals, MVR increased information transfer whenever spike generation required more than one vesicle. This study demonstrates how presynaptic integration of vesicles by MVR can increase the efficiency with which sensory information is transmitted compared with a rate-code described by Poisson statistics.SIGNIFICANCE STATEMENTNeurons communicate by the stochastic release of vesicles at the synapse and the statistics of this process will determine how information is represented by spikes. The classical model is that vesicles are released independently by a Poisson process, but this does not hold at ribbon-type synapses specialized to transmit the first electrical signals in vision and hearing, where two or more vesicles can fuse in a single event by a process termed coordinated multivesicular release. This study shows that multivesicular release can increase the number of spikes generated per vesicle and the efficiency of information transfer (bits per vesicle) over a range of conditions found in the retina and peripheral auditory system.

We demonstrate an artificial efferent nerve that distinguishes environment-responsive conditioned and unconditioned reflexes, i.e., hand-retraction reflex and muscle memory, respectively. These reflex modes are immediately switchable by altering the polarity of charge carriers in a parallel-channeled artificial synapse; this ability emulates multiplexed neurotransmission of different neurotransmitters to form glutamine-induced short-term plasticity and acetylcholine-induced long-term plasticity. This is the successful control of high-strength artificial muscle fibers by using an artificial efferent nerve to form a neuromuscular system that can realize curvature and force simultaneously and in which all these aspects far surpass currently available neuromuscular systems. Furthermore, the special four-quadrant information-processing mechanism of our artificial efferent nerve allows complex application extensions, i.e., relative-position tracking of sound sources, immediate switchable learning modes between fast information processing and long-term memory, and high-accuracy pattern cognition. This work is a step toward development of human-compatible artificial neuromuscular systems.

Brain-derived neurotrophic factor (BDNF) is an important regulator of circuit development, neuronal survival, and plasticity throughout the nervous system. In the visual system, BDNF is produced by retinal ganglion cells (RGCs) and transported along their axons to central targets. Within the dorsolateral geniculate nucleus (dLGN), a key RGC projection target for conscious vision, the BDNF receptor tropomyosin receptor kinase B (TrkB) is present on RGC axon terminals and postsynaptic thalamocortical (TC) relay neuron dendrites. Based on this, the goal of this study was to determine how BDNF modulates the conveyance of signals through the retinogeniculate (RG) pathway of adult mice. Application of BDNF to dLGN brain slices increased TC neuron spiking evoked by optogenetic stimulation of RGC axons. There was a modest contribution to this effect from a BDNF-dependent enhancement of TC neuron intrinsic excitability including increased input resistance and membrane depolarization. BDNF also increased evoked vesicle release from RGC axon terminals, as evidenced by increased amplitude of evoked excitatory postsynaptic currents (EPSCs), which was blocked by inhibition of TrkB or phospholipase C. High-frequency stimulation revealed that BDNF increased synaptic vesicle pool size, release probability, and replenishment rate. There was no effect of BDNF on EPSC amplitude or short-term plasticity of corticothalamic feedback synapses. Thus, BDNF regulates RG synapses by both presynaptic and postsynaptic mechanisms. These findings suggest that BNDF influences the flow of visual information through the retinogeniculate pathway.

Abstract: Neurodegenerative diseases affect over 30 million people worldwide with an ascending trend. Most individuals suffering from these irreversible brain damages belong to the elderly population, with onset between 50 and 60 years. Although the pathophysiology of such diseases is partially known, it remains unclear upon which point a disease turns degenerative. Moreover, current therapeutics can treat some of the symptoms but often have severe side effects and become less effective in long-term treatment. For many neurodegenerative diseases, the involvement of G proteincoupled receptors (GPCRs), which are key players of neuronal transmission and plasticity, has become clearer and holds great promise in elucidating their biological mechanism. With this review, we introduce and summarize class A and class C GPCRs, known to form heterodimers or oligomers to increase their signalling repertoire. Additionally, the examples discussed here were shown to display relevant alterations in brain signalling and had already been associated with the pathophysiology of certain neurodegenerative diseases. Lastly, we classified the heterodimers into two categories of crosstalk, positive or negative, for which there is known evidence.

The interaction between copper ions and amyloid peptide Aβ has been reported to be involved in Alzheimer's disease (AD) pathology. Based on copper coordination biochemistry, we designed specific copper chelators [tetradentate monoquinolines (TDMQs)] in order to regulate copper homeostasis in the AD brain and inhibit the deleterious oxidative stress catalyzed by copper-Aβ complexes. We previously reported that TDMQ20, a highly selective copper chelator selected as a drug candidate, was able to extract copper from the Cu-Aβ

Activating primary afferent TRPV1-positive (TRPV1

Several G-protein coupled receptors (GPCR) are upregulated in Alzheimer's Disease (AD), which ought to facilitate neurotransmission, and improve cognition. Yet, despite this upregulation, associated physiological effects are not observed in AD patients. This paradox solicits urgent attention to find a suitable justification for disturbed neurotransmission in AD. This article focuses on the role of Aβ granules and their possible interaction with GPCRs that modulate neurotransmission and AD progression.

Loss of function of the astrocyte membrane protein MLC1 is the primary genetic cause of the rare white matter disease Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC), which is characterized by disrupted brain ion and water homeostasis. MLC1 is prominently present around fluid barriers in the brain, such as in astrocyte endfeet contacting blood vessels and in processes contacting the meninges. Whether the protein plays a role in other astrocyte domains is unknown. Here, we show that MLC1 is present in distal astrocyte processes, also known as perisynaptic astrocyte processes (PAPs) or astrocyte leaflets, which closely interact with excitatory synapses in the CA1 region of the hippocampus. We find that the PAP tip extending toward excitatory synapses is shortened in Mlc1-null mice. This affects glutamatergic synaptic transmission, resulting in a reduced rate of spontaneous release events and slower glutamate re-uptake under challenging conditions. Moreover, while PAPs in wildtype mice retract from the synapse upon fear conditioning, we reveal that this structural plasticity is disturbed in Mlc1-null mice, where PAPs are already shorter. Finally, Mlc1-null mice show reduced contextual fear memory. In conclusion, our study uncovers an unexpected role for the astrocyte protein MLC1 in regulating the structure of PAPs. Loss of MLC1 alters excitatory synaptic transmission, prevents normal PAP remodeling induced by fear conditioning and disrupts contextual fear memory expression. Thus, MLC1 is a new player in the regulation of astrocyte-synapse interactions.

Diets high in saturated fat (HFD) disrupt dopamine neurotransmission, whereas fasting alters tonic and phasic dopamine release to drive motivation and food consumption. However, functional compartments in the nucleus accumbens (NAc) influencing these effects are not well characterized, and sex comparisons have not been made. This study sought to determine whether consumption of a HFD, sex, or being fed versus fasted altered baseline dopamine release and reuptake throughout NAc subregions. Male and female C57BL/6 mice were fed a control diet or nutrient matched HFD for six weeks. Ex-vivo fast-scan cyclic voltammetry revealed females had significantly slower dopamine reuptake in the NAc core than males when fed ad lib control diet. Fasting enhanced dopamine release and reuptake in the NAc core but not the medioventral shell. Further, being fasted versus fed significantly increased dopamine release throughout the NAc core in control males but specifically promoted release and reuptake in only the ventrolateral core of HF-fed males, effects which were lacking in females. Finally, fasting promoted dopamine release and reuptake in the rostral NAc core of controls and more caudally in HFD groups. These data support that dopamine neurotransmission is heterogeneous in NAc subregions and suggest the ventrolateral core is responsive to energy state. Furthermore, a rostrocaudal gradient in the NAc core might control valence responses to fasting that could promote overeating after chronic HFD consumption.

Enteric neurotransmission is critical for coordinating motility throughout the gastrointestinal (GI) tract. However, there is considerable controversy regarding the cells that are responsible for the transduction of these neural inputs. In the present study, utilization of a cell-specific calcium biosensor GCaMP6f, the spontaneous activity and neuroeffector responses of intramuscular ICC (ICC-IM) to motor neural inputs was examined. Simultaneous intracellular microelectrode recordings and high-speed video-imaging during nerve stimulation was used to reveal the temporal relationship between changes in intracellular Ca

Background and PurposeDonepezil, a piperidine antagonist of acetylcholinesterase (AChE) prescribed for treatment of Alzheimer’s Disease, has adverse neuromuscular effects in humans, including requirement for higher concentrations of non-depolarising neuromuscular blockers during surgery. Here we examined the effects of donepezil on synaptic transmission at neuromuscular junctions (NMJs) in isolated nerve-muscle preparations from mice.Experimental ApproachWe measured effects of therapeutic concentrations of donepezil (10nM-1 μM) on AChE enzymic activity, muscle force responses to repetitive stimulation, and spontaneous and evoked endplate potentials (EPPs) recorded intracellularly from flexor digitorum brevis muscles.Key ResultsDonepezil inhibited muscle AChE with an approximate IC50 of 30 nM. Tetanic stimulation in sub-micromolar concentrations of donepezil caused prolonged post-tetanic muscle contractions. Preliminary Fluo4-imaging indicated an association of these contractions with an increase and slow decay of intracellular Ca2+ transients at motor endplates. Donepezil prolonged spontaneous MEPP decay time constant by about 65% and extended evoked EPP duration by a factor of almost three. The mean frequency of spontaneous MEPPs was unaffected but the incidence of “giant” MEPPs (gMEPPs), some exceeding 10 mV in amplitude, was increased. Neither mean MEPP amplitude (excluding gMEPPs), mean EPP amplitude, quantal content, or synaptic depression during repetitive stimulation were significantly altered by concentrations of donepezil up to 1 μM.Conclusion and ImplicationsAdverse neuromuscular signs associated with donepezil therapy, including relative insensitivity to neuromuscular blockers, are likely due to inhibition of AChE at NMJs, prolonging the action of ACh on their postsynaptic nicotinic acetylcholine receptors but without substantively impairing evoked ACh release.

Endocannabinoids (eCBs) are lipid neuromodulators that suppress neurotransmitter release, reduce postsynaptic excitability, activate astrocyte signaling, and control cellular respiration. Here, we describe canonical and emerging eCB signaling modes and aim to link adaptations in these signaling systems to pathological states. Adaptations in eCB signaling systems have been identified in a variety of biobehavioral and physiological process relevant to neuropsychiatric disease states including stress-related disorders, epilepsy, developmental disorders, obesity, and substance use disorders. These insights have enhanced our understanding of the pathophysiology of neurological and psychiatric disorders and are contributing to the ongoing development of eCB-targeting therapeutics. We suggest future studies aimed at illuminating how adaptations in canonical as well as emerging cellular and synaptic modes of eCB signaling contribute to disease pathophysiology or resilience could further advance these novel treatment approaches.

Tonotopic organization is a fundamental feature of the auditory system. In the developing auditory brainstem, the ontogeny and maturation of neurotransmission progress from high to low frequencies along the tonotopic axis. To explore the underlying mechanism of this tonotopic development, we aim to determine whether the presynaptic machinery responsible for neurotransmitter release is tonotopically differentiated during development. In the current study, we examined vesicular neurotransmitter transporters and calcium sensors, two central players responsible for loading neurotransmitter into synaptic vesicles and for triggering neurotransmitter release in a calcium-dependent manner, respectively. Using immunocytochemistry, we characterized the distribution patterns of vesicular glutamate transporters (VGLUTs) 1 and 2, vesicular gamma-aminobutyric acid transporter (VGAT), and calcium sensor synaptotagmin (Syt) 1 and 2 in the developing mouse medial nucleus of the trapezoid body (MNTB). We identified tonotopic gradients of VGLUT1, VGAT, Syt1, and Syt2 in the first postnatal week, with higher protein densities in the more medial (high-frequency) portion of the MNTB. These gradients gradually flattened before the onset of hearing. In contrast, VGLUT2 was distributed relatively uniformly along the tonotopic axis during this prehearing period. In mice lacking Fragile X mental retardation protein, an mRNA-binding protein that regulates synaptic development and plasticity, progress to achieve the mature-like organization was altered for VGLUT1, Syt1, and Syt2, but not for VGAT. Together, our results identified novel organization patterns of selective presynaptic proteins in immature auditory synapses, providing a potential mechanism that may contribute to tonotopic differentiation of neurotransmission during normal and abnormal development.

The basolateral nucleus of the amygdala (BLA) plays an important role in the development of fear and anxiety-related behaviors. The BLA receives inputs from all sensory stimuli. After processing those stimuli, BLA neurons signal neurons within the central amygdala and other brain regions, including the ventral and dorsal striatum and frontal cortex. Studies suggest that the BLA is involved in drug dependence and in the reinforcing actions of ethanol. For example, acute exposure to ethanol reduces anxiety, while withdrawal from chronic ethanol exposure alters BLA synaptic transmission, which increases anxiety, a common underlying cause of relapse. Exposure to and withdrawal from chronic alcohol also disrupts many brain areas that connect with the BLA. Despite these important findings, the acute actions of alcohol on the intrinsic excitability of BLA neurons have not been fully characterized.Brain slices containing the BLA were prepared from adult C57BL/6J male mice. Whole-cell and sharp electrode electrophysiological recordings were performed to characterize the effects of acute ethanol on BLA neuronal and astrocyte function, respectively.Ethanol inhibited action potential (AP) firing of BLA neurons but had no effect on BLA astrocyte resting membrane potential. The ethanol-induced inhibition of firing was concentration-dependent (11 to 66 mM) and accompanied by a reduction in the input resistance and an increase in the rheobase of BLA neurons. The inhibitory effect of ethanol was suppressed by picrotoxin, which blocks both γ-aminobutyric acid type A (GABAThese results suggest that BLA neurons express a GABA-mediated tonic current that is enhanced by acute ethanol, which leads to reduced excitability of BLA neurons.

Ion channels are targets of considerable therapeutic interest to address a wide variety of neurologic indications, including pain perception. Current pharmacological strategies have focused mostly on small molecule approaches that can be limited by selectivity requirements within members of a channel family or superfamily. Therapeutic antibodies have been proposed, designed, and characterized to alleviate this selectivity limitation; however, there are no Food and Drug Administration-approved therapeutic antibody-based drugs targeting ion channels on the market to date. Here, in an effort to identify novel classes of engineered ion channel modulators for potential neurologic therapeutic applications, we report the generation and characterization of six (EC

Per- and polyfluoroalkyl substances (PFAS) are a group of persistent environmental pollutants that are ubiquitously found in the environment and virtually in all living organisms, including humans. PFAS cross the blood-brain barrier and accumulate in the brain. Thus, PFAS are a likely risk for neurotoxicity. Studies that measured PFAS levels in the brains of humans, polar bears, and rats have demonstrated that some areas of the brain accumulate greater amounts of PFAS. Moreover, in humans, there is evidence that PFAS exposure is associated with attention-deficit/hyperactivity disorder (ADHD) in children and an increased cause of death from Parkinson's disease and Alzheimer's disease in elderly populations. Given possible links to neurological disease, critical analyses of possible mechanisms of neurotoxic action are necessary to advance the field. This paper critically reviews studies that investigated potential mechanistic causes for neurotoxicity including (1) a change in neurotransmitter levels, (2) dysfunction of synaptic calcium homeostasis, and (3) alteration of synaptic and neuronal protein expression and function. We found growing evidence that PFAS exposure causes neurotoxicity through the disruption of neurotransmission, particularly the dopamine and glutamate systems, which are implicated in age-related psychiatric illnesses and neurodegenerative diseases. Evaluated research has shown there are highly reproduced increased glutamate levels in the hippocampus and catecholamine levels in the hypothalamus and decreased dopamine in the whole brain after PFAS exposure. There are significant gaps in the literature relative to the assessment of the nigrostriatal system (striatum and ventral midbrain) among other regions associated with PFAS-associated neurologic dysfunction observed in humans. In conclusion, evidence suggests that PFAS may be neurotoxic and associated with chronic and age-related psychiatric illnesses and neurodegenerative diseases. Thus, it is imperative that future mechanistic studies assess the impact of PFAS and PFAS mixtures on the mechanism of neurotransmission and the consequential functional effects.

Endemic arsenism is a worldwide health problem. Chronic arsenic exposure results in cognitive dysfunction due to arsenic and its metabolites accumulating in hippocampus. As the cellular basis of cognition, synaptic plasticity is pivotal in arsenic-induced cognitive dysfunction. N-methyl-D-aspartate receptors (NMDARs) serve physiological functions in synaptic transmission. However, excessive NMDARs activity contributes to exitotoxicity and synaptic plasticity impairment. Here, we provide an overview of the mechanisms that NMDARs and their downstream signaling pathways mediate synaptic plasticity impairment due to arsenic exposure in hippocampal neurons, ways of arsenic exerting on NMDARs, as well as the potential therapeutic targets except for water improvement.

Systemic nicotine administration regulates neuronal activities in mouse auditory cortex. How nicotine regulates the spread of the activities across auditory cortical areas is not well known. We investigate this using flavoprotein fluorescence imaging. 20 kHz amplitude-modulated (AM) tones increased the peak intensity of flavoprotein fluorescence in presumptive primary auditory cortex (A1). 5 kHz AM tones activated at least three cortical areas, which are presumably A1, anterior auditory field, and secondary auditory cortex. Nicotine enlarged tone-activated cortical areas and enhanced both 20 kHz and 5 kHz tone-evoked fluorescence intensities at their respective, optimal frequency peak sites and at non-optimal frequency peak sites in A1. The extent of this enhancement was greater at non-optimal frequency sites than at optimal frequency sites. A cortical injection of dihydro-β-erythroidine, an inhibitor of nicotinic acetylcholine receptors composed of α4 and β2-subunits (α4β2*-nAChRs), blocked the enhancement of fluorescence intensity at the peak sites but did not appear to block the enlargement of activated areas. These results suggest that nicotine exposure activates cortical α4β2*-nAChRs to enhance tone-evoked local neuronal activities at an optimal frequency site. The nicotine-induced enlargement of a tone-activated area may depend on the nicotinic enhancement of cortical inputs or other activities.

Objective. The current study aims to analyze the improvement mechanism of visceral hypersensitivity (VH) and targets of Shugan Jiangni Hewei granules (SJHG) for nonerosive reflux disease (NERD) treatment as well as to offer an experimental foundation for its clinical use. Methods. Healthy male Sprague–Dawley rats ( n = 36) were acquired in the current study that was further split into three groups: blank, model, and drug (SJHG). Subsequently, differentially expressed proteins and bioinformatics analysis were performed on the collected tissue samples acquired from the anterior cingulate cortex of the model and SJHG rat groups using a tandem mass tag- (TMT-) based proteomics. Eventually, the obtained data from the bioinformatic analysis was further verified through western blotting. Results. From the bioinformatics analysis, only 64 proteins were differentially expressed between the NC and SJHG groups. These molecules were found to be highly expressed in immunological response and neural signal transmission. Finally, we confirmed three therapeutic targets of SJHG, namely, kininogen 1 (Kng1), junctional adhesion molecule A (JAM-A), and the PI3K/Akt signaling pathway. Conclusions. SJHG is effective in treating VH, Kng1 and JAM-A may be therapeutic targets of SJHG, and the therapeutic mechanism of SJHG may be realized by influencing immune response or transmission of neural signals.

Retinal bipolar cells (BCs) compose the canonical vertical excitatory pathway that conveys photoreceptor output to inner retinal neurons. Although synaptic transmission from BC terminals is thought to rely almost exclusively on Ca(2+) influx through voltage-gated Ca(2+) (Ca(V)) channels mediating L-type currents, the molecular identity of Ca(V) channels in BCs is uncertain. Therefore, we combined molecular and functional analyses to determine the expression profiles of Ca(V) α(1), β, and α(2)δ subunits in mouse rod bipolar (RB) cells, BCs from which the dynamics of synaptic transmission are relatively well-characterized. We found significant heterogeneity in Ca(V) subunit expression within the RB population from mice of either sex, and significantly, we discovered that transmission from RB synapses was mediated by Ca(2+) influx through P/Q-type (Ca(V)2.1) and N-type (Ca(V)2.2) conductances as well as the previously-described L-type (Ca(V)1) and T-type (Ca(V)3) conductances. Furthermore, we found both Ca(V)1.3 and Ca(V)1.4 proteins located near presynaptic ribbon-type active zones in RB axon terminals, indicating that the L-type conductance is mediated by multiple Ca(V)1 subtypes. Similarly, Ca(V)3 α(1), β, and α(2)δ subunits also appear to obey a “multisubtype” rule, i.e., we observed a combination of multiple subtypes, rather than a single subtype as previously thought, for each Ca(V) subunit in individual cells. SIGNIFICANCE STATEMENT Bipolar cells (BCs) transmit photoreceptor output to inner retinal neurons. Although synaptic transmission from BC terminals is thought to rely almost exclusively on Ca(2+) influx through L-type voltage-gated Ca(2+) (Ca(V)) channels, the molecular identity of Ca(V) channels in BCs is uncertain. Here, we report unexpectedly high molecular diversity of Ca(V) subunits in BCs. Transmission from rod bipolar (RB) cell synapses can be mediated by Ca(2+) influx through P/Q-type (Ca(V)2.1) and N-type (Ca(V)2.2) conductances as well as the previously-described L-type (Ca(V)1) and T-type (Ca(V)3) conductances. Furthermore, Ca(V)1, Ca(V)3, β, and α(2)δ subunits appear to obey a “multisubtype” rule, i.e., a combination of multiple subtypes for each subunit in individual cells, rather than a single subtype as previously thought.

The nervous system is important, because it regulates the physiological function of the body. Neurons are the most basic structural and functional unit of the nervous system. The synapse is an asymmetric structure that is important for neuronal function. The chemical transmission mode of the synapse is realized through neurotransmitters and electrical processes. Based on vesicle transport, the abnormal information transmission process in the synapse can lead to a series of neurorelated diseases. Numerous proteins and complexes that regulate the process of vesicle transport, such as SNARE proteins, Munc18-1, and Synaptotagmin-1, have been identified. Their regulation of synaptic vesicle secretion is complicated and delicate, and their defects can lead to a series of neurodegenerative diseases. This review will discuss the structure and functions of vesicle-based synapses and their roles in neurons. Furthermore, we will analyze neurotransmitter and synaptic functions in neurodegenerative diseases and discuss the potential of using related drugs in their treatment.

Rett syndrome is a leading cause of intellectual disability in females primarily caused by loss of function mutations in the transcriptional regulator MeCP2. Loss of MeCP2 leads to a host of synaptic phenotypes that are believed to underlie Rett syndrome pathophysiology. Synaptic deficits vary by brain region upon MeCP2 loss, suggesting distinct molecular alterations leading to disparate synaptic outcomes. In this study, we examined the contribution of MeCP2's newly described role in miRNA regulation to regional molecular and synaptic impairments. Two miRNAs, miR-101a and miR-203, were identified and confirmed as upregulated in MeCP2 KO mice in the hippocampus and cortex, respectively. miR-101a overexpression in hippocampal cultures led to opposing effects at excitatory and inhibitory synapses and in spontaneous and evoked neurotransmission, revealing the potential for a single miRNA to broadly regulate synapse function in the hippocampus. These results highlight the importance of regional alterations in miRNA expression and the specific impact on synaptic function with potential implications for Rett syndrome.

Synaptic transmission constitutes the primary mode of communication between neurons. It is extensively studied in rodent but not human neocortex. We characterized synaptic transmission between pyramidal neurons in layers 2 and 3 using neurosurgically resected human middle temporal gyrus (MTG, Brodmann area 21), which is part of the distributed language circuitry. We find that local connectivity is comparable with mouse layer 2/3 connections in the anatomical homologue (temporal association area), but synaptic connections in human are 3-fold stronger and more reliable (0% vs 25% failure rates, respectively). We developed a theoretical approach to quantify properties of spinous synapses showing that synaptic conductance and voltage change in human dendritic spines are 3–4-folds larger compared with mouse, leading to significant NMDA receptor activation in human unitary connections. This model prediction was validated experimentally by showing that NMDA receptor activation increases the amplitude and prolongs decay of unitary excitatory postsynaptic potentials in human but not in mouse connections. Since NMDA-dependent recurrent excitation facilitates persistent activity (supporting working memory), our data uncovers cortical microcircuit properties in human that may contribute to language processing in MTG.

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P(r)). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P(r), suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P(r), which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure. SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.

Methamphetamine (METH) abuse is associated with the emergence of cognitive deficits and hypofrontality, a pathophysiological marker of many neuropsychiatric disorders that is produced by altered balance of local excitatory and inhibitory synaptic transmission. However, there is a dearth of information regarding the cellular and synaptic mechanisms underlying METH-induced cognitive deficits and associated hypofrontal states. Using PV-Cre transgenic rats that went through a METH sensitization regime or saline (SAL) followed by 7-10 days of home cage abstinence combined with cognitive tests, chemogenetic experiments, and whole-cell patch recordings on the prelimbic prefrontal cortex (PFC), we investigated the cellular and synaptic mechanisms underlying METH-induce hypofrontality. We report here that repeated METH administration in rats produces deficits in working memory and increases in inhibitory synaptic transmission onto pyramidal neurons in the PFC. The increased PFC inhibition is detected by an increase in spontaneous and evoked inhibitory postsynaptic synaptic currents (IPSCs), an increase in GABAergic presynaptic function, and a shift in the excitatory-inhibitory balance onto PFC deep-layer pyramidal neurons. We find that pharmacological blockade of D1 dopamine receptor function reduces the METH-induced augmentation of IPSCs, suggesting a critical role for D1 dopamine signaling in METH-induced hypofrontality. In addition, repeated METH administration increases the intrinsic excitability of parvalbumin-positive fast spiking interneurons (PV + FSIs), a key local interneuron population in PFC that contributes to the control of inhibitory tone. Using a cell type-specific chemogenetic approach, we show that increasing PV + FSIs activity in the PFC is necessary and sufficient to cause deficits in temporal order memory similar to those induced by METH. Conversely, reducing PV + FSIs activity in the PFC of METH-exposed rats rescues METH-induced temporal order memory deficits. Together, our findings reveal that repeated METH exposure increases PFC inhibitory tone through a D1 dopamine signaling-dependent potentiation of inhibitory synaptic transmission, and that reduction of PV + FSIs activity can rescue METH-induced cognitive deficits, suggesting a potential therapeutic approach to treating cognitive symptoms in patients suffering from METH use disorder.

Cellular and network properties must be capable of generating rhythmic activity that is both flexible and stable. This is particularly important for breathing, a rhythmic behavior that dynamically adapts to environmental, behavioral, and metabolic changes from the first to the last breath. The pre-Bötzinger complex (preBötC), located within the ventral medulla, is responsible for producing rhythmic inspiration. Its cellular properties must be tunable, flexible as well as stabilizing. Here, we explore the role of the hyperpolarization-activated, nonselective cation current (I(h)) for stabilizing PreBötC activity during opioid exposure and reduced excitatory synaptic transmission. Introducing I(h) into an in silico preBötC network predicts that loss of this depolarizing current should significantly slow the inspiratory rhythm. By contrast, in vitro and in vivo experiments revealed that the loss of I(h) minimally affected breathing frequency, but destabilized rhythmogenesis through the generation of incompletely synchronized bursts (burstlets). Associated with the loss of I(h) was an increased susceptibility of breathing to opioid-induced respiratory depression or weakened excitatory synaptic interactions, a paradoxical depolarization at the cellular level, and the suppression of tonic spiking. Tonic spiking activity is generated by nonrhythmic excitatory and inhibitory preBötC neurons, of which a large percentage express I(h). Together, our results suggest that I(h) is important for maintaining tonic spiking, stabilizing inspiratory rhythmogenesis, and protecting breathing against perturbations or changes in network state. NEW & NOTEWORTHY The I(h) current plays multiple roles within the preBötC. This current is important for promoting intrinsic tonic spiking activity in excitatory and inhibitory neurons and for preserving rhythmic function during conditions that dampen network excitability, such as in the context of opioid-induced respiratory depression. We therefore propose that the I(h) current expands the dynamic range of rhythmogenesis, buffers the preBötC against network perturbations, and stabilizes rhythmogenesis by preventing the generation of unsynchronized bursts.

The nucleus tractus solitarii (nTS) is the major integrative brainstem region for autonomic modulation and processing of cardiovascular reflexes. GABA and glutamate are the main inhibitory and excitatory neurotransmitters, respectively, within this nucleus. Alterations in the GABA-glutamate regulation in the nTS are related to numerous cardiovascular comorbidities. Bedridden individuals and people exposed to microgravity exhibit dysautonomia and cardiovascular deconditioning that are mimicked in the hindlimb unloading (HU) rat model. We have previously shown in the nTS that HU increases glutamatergic neurotransmission yet decreases neuronal excitability. In this study, we investigated the effects of HU on nTS GABAergic neurotransmission. We hypothesized that HU potentiates GABA signaling via increased GABAergic release and postsynaptic GABA receptor expression. Following HU or control postural exposure, GABAergic neurotransmission was assessed using whole cell patch clamp whereas the magnitude of GABA release was evaluated via an intensity-based GABA sensing fluorescence reporter (iGABASnFR). In response to GABA interneuron stimulation, the evoked inhibitory postsynaptic current (nTS-IPSC) amplitude and area, as well as iGABASnFR fluorescence, were greater in HU than in control. HU also elevated the frequency but not the amplitude of spontaneous miniature IPSCs. Picoapplication of GABA produced similar postsynaptic current responses in nTS neurons of HU and control. Moreover, HU did not alter GABA(A) receptor α1 subunit expression, indicating minimal alterations in postsynaptic membrane receptor expression. These results indicate that HU increases GABAergic signaling in the nTS likely via augmented release of GABA from presynaptic terminals. Altogether, our data indicate GABA plasticity contributes to the autonomic and cardiovascular alterations following cardiovascular deconditioning (CVD). NEW & NOTEWORTHY Gravity influences distribution of blood volume and autonomic function. Microgravity and prolonged bed rest induce cardiovascular deconditioning (CVD). We used hindlimb unloading (HU), a rat analog for bed rest, to investigate CVD-induced neuroplasticity in the brainstem. Our data demonstrate that HU increases GABA modulation of nucleus tractus solitarii (nTS) neurons via presynaptic plasticity. Given the importance of nTS in integrating cardiovascular reflexes, this study provides new evidence on the central mechanisms behind CVD following HU.

The fluorescent glutamate indicator iGluSnFR enables imaging of neurotransmission with genetic and molecular specificity. However, existing iGluSnFR variants exhibit low in vivo signal-to-noise ratios, saturating activation kinetics and exclusion from postsynaptic densities. Using a multiassay screen in bacteria, soluble protein and cultured neurons, we generated variants with improved signal-to-noise ratios and kinetics. We developed surface display constructs that improve iGluSnFR's nanoscopic localization to postsynapses. The resulting indicator iGluSnFR3 exhibits rapid nonsaturating activation kinetics and reports synaptic glutamate release with decreased saturation and increased specificity versus extrasynaptic signals in cultured neurons. Simultaneous imaging and electrophysiology at individual boutons in mouse visual cortex showed that iGluSnFR3 transients report single action potentials with high specificity. In vibrissal sensory cortex layer 4, we used iGluSnFR3 to characterize distinct patterns of touch-evoked feedforward input from thalamocortical boutons and both feedforward and recurrent input onto L4 cortical neuron dendritic spines.

Local stimulation of tissue can occur naturally in events like immune-mediated inflammation and focal ischemic injuries in brain and is confined to specific regions within tissue, occurring on various timescales. Making chemical measurements at the exact site of stimulation with current technologies is difficult yet important for understanding tissue response. We have developed a microfluidic device capable of local stimulation of brain slices with minimal lateral spread over time and submillimeter, tunable spatial resolution. This device is compatible with electrochemical measurements to monitor signaling at the site of stimulation over time. The PDMS-based device is three layers and contains a culture well, channel layer, and exit port layer for the channels. Channels with exit ports straddling the stimulus channels and ports were specifically fabricated to focus the stimulus over time. We demonstrated that the device is compatible with fast-scan cyclic voltammetry (FSCV) recording of neurotransmitter release. Localized hypoxia in tissue was verified using Image-iT Green Hypoxia Reagent and coupling this device with FSCV enabled measurement of local dopamine changes at the site of focal ischemia for the first time. This work provides a significant advance in knowledge of local neurochemical fluctuations during sustained tissue injury. Overall, the unique capabilities of the device to deliver sustained localized stimulation combined with real-time sensing provide an innovative platform to answer significant biological questions about how tissues respond at the site of controlled, localized injury and chemical stimulation.

Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here, we show that the loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis targeting RIPK3 in aged mice, reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline.

The ability of neurons to dynamically and flexibly encode synaptic inputs via short- and long-term plasticity is critical to an organism's ability to learn and adapt to the environment. Whereas synaptic plasticity may be encoded by pre- or postsynaptic mechanisms, current evidence suggests that optimization of learning requires both forms of plasticity. Endogenous cannabinoids (eCBs) play critical roles in modulating synaptic transmission via activation of cannabinoid CB1 receptors (CB1Rs) in many central nervous system (CNS) regions, and the eCB system has been implicated, either directly or indirectly, in several forms of synaptic plasticity. Because of this, perturbations within the eCB signaling system can lead to impairments in a variety of learned behaviors. One agent of altered eCB signaling is exposure to "exogenous cannabinoids" such as the primary psychoactive constituent of cannabis, Δ

In spinal muscular atrophy (SMA), mutations in or loss of the Survival Motor Neuron 1 (SMN1) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca2+ transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands.

Terahertz waves lie within the rotation and oscillation energy levels of biomolecules, and can directly couple with biomolecules to excite nonlinear resonance effects, thus causing conformational or configuration changes in biomolecules. Based on this mechanism, we investigated the effect pattern of 0.138 THz radiation on the dynamic growth of neurons and synaptic transmission efficiency, while explaining the phenomenon at a more microscopic level. We found that cumulative 0.138 THz radiation not only did not cause neuronal death, but that it promoted the dynamic growth of neuronal cytosol and protrusions. Additionally, there was a cumulative effect of terahertz radiation on the promotion of neuronal growth. Furthermore, in electrophysiological terms, 0.138 THz waves improved synaptic transmission efficiency in the hippocampal CA1 region, and this was a slow and continuous process. This is consistent with the morphological results. This phenomenon can continue for more than 10 min after terahertz radiation ends, and these phenomena were associated with an increase in dendritic spine density. In summary, our study shows that 0.138 THz waves can modulate dynamic neuronal growth and synaptic transmission. Therefore, 0.138 terahertz waves may become a novel neuromodulation technique for modulating neuron structure and function.

The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

Thyrotropin-releasing hormone (TRH) and the TRH mimetic taltirelin have been used in Japan for the treatment of spinocerebellar degeneration (SCD), a type of progressive ataxia. A TRH mimetic, rovatirelin, ameliorates ataxia symptoms in the rolling mouse Nagoya, a hereditary SCD model. The aim of this study was to verify the effects of oral administration of rovatirelin on a cytosine arabinoside (Ara-C)-induced ataxia rat model, a sporadic SCD model characterized by gait abnormalities and falls because of cerebellar atrophy and investigate the central nervous system mechanism associated with rovatirelin-mediated amelioration of motor dysfunction in these rats. Rovatirelin at ≥3 mg/kg significantly decreased the fall index, which is a primary endpoint of improved motor function calculated by dividing the number of falls by the locomotor activity, in both male and female rats with Ara-C-induced ataxia. Furthermore, rovatirelin caused a significant increase in locomotor activity in a dose-dependent manner. Taltirelin at ≥30 mg/kg ameliorated motor dysfunction in ataxic rats. Moreover, rovatirelin significantly increased acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and dopamine (DA) levels in the nucleus accumbens (NAc) at ≥3 mg/kg and significantly increased DA levels in the dorsal striatum at ≥10 mg/kg in normal rats. In conclusion, oral administration of rovatirelin ameliorates motor dysfunction in rats with Ara-C-induced ataxia, owing to its ACh-increasing effects in the mPFC and DA-increasing effects in the dorsal striatum and NAc. Furthermore, the effects of rovatirelin were more potent than those of taltirelin.

For many decades, synaptic plasticity was believed to be restricted to excitatory transmission. However, in recent years, this view started to change, and now it is recognized that GABAergic synapses show distinct forms of activity-dependent long-term plasticity, but the underlying mechanisms remain obscure. Herein, we asked whether signaling mediated by β1 or β3 subunit-containing integrins might be involved in regulating the efficacy of GABAergic synapses, including the NMDA receptor-dependent inhibitory long-term potentiation (iLTP) in the hippocampus. We found that activation of β3 integrin with fibrinogen induced a stable depression, whereas inhibition of β1 integrin potentiated GABAergic synapses at CA1 pyramidal neurons in male mice. Additionally, compounds that interfere with the interaction of β1 or β3 integrins with extracellular matrix blocked the induction of NMDA-iLTP. In conclusion, we provide the first evidence that integrins are key players in regulating the endogenous modulatory mechanisms of GABAergic inhibition and plasticity in the hippocampus. SIGNIFICANCE STATEMENT Epilepsy, schizophrenia, and anxiety are just a few medical conditions associated with dysfunctional inhibitory synaptic transmission. GABAergic synapses are known for their extraordinary susceptibility to modulation by endogenous factors and exogenous pharmacological agents. We describe here that integrins, adhesion proteins, play a key role in the modulation of inhibitory synaptic transmission. Specifically, we show that interference with integrin-dependent adhesion results in a variety of effects on the amplitude and frequency of GABAergic mIPSCs. Activation of β3 subunit-containing integrins induces inhibitory long-term depression, whereas the inhibition of β1 subunit-containing integrins induces iLTP. Our results unveil an important mechanism controlling synaptic inhibition, which opens new avenues into the usage of integrin-aimed pharmaceuticals as modulators of GABAergic synapses.

Early-life social isolation is associated with social and emotional problems in adulthood. However, neural mechanisms underlying how social deprivation impairs social and emotional development are poorly understood. Recently, the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) have been highlighted as key nodes for social and emotional functions. Hence, we hypothesize that early social deprivation disrupts the information processing in the OFC-BLA pathway and leads to social and emotional dysfunction. Here, we examined the effects of adolescent social isolation on the OFC-BLA synaptic transmission by optogenetic and whole-cell patch-clamp methods in adult mice. Adolescent social isolation decreased social preference and increased passive stress-coping behaviour in adulthood. Then, we examined excitatory synaptic transmissions to BLA from medial or lateral subregions of the OFC (mOFC or lOFC). Notably, adolescent social isolation decreased the AMPA/NMDA ratio in the mOFC-BLA synapse in adulthood, while the ratio was increased in the lOFC-BLA synapse. Furthermore, we optogenetically manipulated the mOFC-BLA or lOFC-BLA transmission in behaving mice and examined the effects on social and stress-coping behaviours. Optogenetic manipulation of the mOFC-BLA transmission altered social behaviour without affecting passive stress-coping behaviour, while optogenetic manipulation of the lOFC-BLA transmission altered passive stress-coping behaviour without affecting social behaviour. Our results suggest that adolescent social isolation induces distinct postsynaptic changes in the mOFC-BLA and lOFC-BLA synapses, and these changes may separately contribute to abnormalities in social and emotional development.

Dopamine (DA) and glutamate neurotransmission are strongly implicated in schizophrenia pathophysiology. While most studies focus on contributions of neurons that release only DA or glutamate, neither DA nor glutamate models alone recapitulate the full spectrum of schizophrenia pathophysiology. Similarly, therapeutic strategies limited to either system cannot effectively treat all three major symptom domains of schizophrenia: positive, negative, and cognitive symptoms. Increasing evidence suggests extensive interactions between the DA and glutamate systems and more effective treatments may therefore require the targeting of both DA and glutamate signaling. This offers the possibility that disrupting DA-glutamate circuitry between these two systems, particularly in the striatum and forebrain, culminate in schizophrenia pathophysiology. Yet, the mechanisms behind these interactions and their contributions to schizophrenia remain unclear. In addition to circuit- or system-level interactions between neurons that solely release either DA or glutamate, here we posit that functional alterations involving a subpopulation of neurons that co-release both DA and glutamate provide a novel point of integration between DA and glutamate systems, offering a key missing link in our understanding of schizophrenia pathophysiology. Better understanding of mechanisms underlying DA/glutamate co-release from these neurons may therefore shed new light on schizophrenia pathophysiology and lead to more effective therapeutics.

Synaptic transmission via neurochemical release is the fundamental process that integrates and relays encoded information in the brain to regulate physiological function, cognition, and emotion. To unravel the biochemical, biophysical, and computational mechanisms of signal processing, one needs to precisely measure the neurochemical release dynamics with molecular and cell-type specificity and high resolution. Here we reviewed the development of analytical, electrochemical, and fluorescence imaging approaches to detect neurotransmitter and neuromodulator release. We discussed the advantages and practicality in implementation of each technology for ease-of-use, flexibility for multimodal studies, and challenges for future optimization. We hope this review will provide a versatile guide for tool engineering and applications for recording neurochemical release.

Mild traumatic brain injury (mTBI) or concussion is the most common form of TBI which frequently results in persistent cognitive impairments and memory deficits in affected individuals [1]. Although most studies have investigated the role of hippocampal synaptic dysfunction in earlier time points following a single injury, the long-lasting effects of mTBI on hippocampal synaptic transmission following multiple brain concussions have not been well-elucidated. Using a repetitive closed head injury (3XCHI) mouse model of mTBI, we examined the alteration of spontaneous synaptic transmission onto hippocampal CA1 pyramidal neurons by recording spontaneous excitatory AMPA receptor (AMPAR)- and inhibitory GABAAR-mediated postsynaptic currents (sEPSCs and sIPSCs, respectively) in adult male mice 2-weeks following the injury. We found that mTBI potentiated postsynaptic excitatory AMPAR synaptic function while depressed postsynaptic inhibitory GABAAR synaptic function in CA1 pyramidal neurons. Additionally, mTBI slowed the decay time of AMPAR currents while shortened the decay time of GABAAR currents suggesting changes in AMPAR and GABAAR subunit composition by mTBI. On the other hand, mTBI reduced the frequency of sEPSCs while enhanced the frequency of sIPSCs resulting in a lower ratio of sEPSC/sIPSC frequency in CA1 pyramidal neurons of mTBI animals compared to sham animals. Altogether, our results suggest that mTBI induces persistent postsynaptic modifications in AMPAR and GABAAR function and their synaptic composition in CA1 neurons while triggering a compensatory shift in excitation/inhibition (E/I) balance of presynaptic drives towards more inhibitory synaptic drive to hippocampal CA1 cells. The persistent mTBI-induced CA1 synaptic dysfunction and E/I imbalance could contribute to deficits in hippocampal plasticity that underlies long-term hippocampal-dependent learning and memory deficits in mTBI patients long after the initial injury.

The rostral thalamic reticular nucleus (rTRN) exerts the same inhibitory control of thalamocortical transmission from the motor nuclei as the caudal sectors have over sensory nuclei. It is well established that the caudal sectors are involved in selective attention. This suggests an analogous role for rTRN in the selection of situationally appropriate behavior. Rats were trained to make an observing response followed by the illumination one of two centrally located light emitting diodes (LEDs) signaling the location of the correct nose poke to the left or right. Unilateral injections of ibotenic acid or saline were aimed at the rTRN. Postoperatively, the proportion of incorrect responses made into the hole contralateral to the lesion increased, and there was a concomitant decline in the number of correct responses directed ipsilateral to the lesion when compared with the rats with sham surgeries. Basic sensory and motor deficits do not account for these effects because response times and uncued responses did not differ between the groups. The data suggest that the diminished inhibition of the motor nuclei on the side of the rTRN lesion weakened the ability to deselect the incorrect contralateral response. We propose that the sensory and motor sectors of the TRN are functionally similar and the rTRN increases the contrast between a selected and nonselected actions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Imaging of dopaminergic transmission in neurodegenerative disorders such as Parkinson disease (PD) or dementia with Lewy bodies plays a major role in clinical practice and in clinical research. We here review the role of imaging of the nigrostriatal pathway, as well as of striatal receptors and dopamine release, in common neurodegenerative disorders in clinical practice and research. Imaging of the nigrostriatal pathway has a high diagnostic accuracy to detect nigrostriatal degeneration in disorders characterized by nigrostriatal degeneration, such as PD and dementia with Lewy bodies, and disorders of more clinical importance, namely in patients with clinically uncertain parkinsonism. Imaging of striatal dopamine D2/3 receptors is not recommended for the differential diagnosis of parkinsonian disorders in clinical practice anymore. Regarding research, recently the European Medicines Agency has qualified dopamine transporter imaging as an enrichment biomarker for clinical trials in early PD, which underlines the high diagnostic accuracy of this imaging tool and will be implemented in future trials. Also, imaging of the presynaptic dopaminergic system plays a major role in, for example, examining the extent of nigrostriatal degeneration in preclinical and premotor phases of neurodegenerative disorders and to examine subtypes of PD. Also, imaging of postsynaptic dopamine D2/3 receptors plays a role in studying, for example, the neuronal substrate of impulse control disorders in PD, as well as in measuring endogenous dopamine release to examine, for example, motor complications in the treatment of PD. Finally, novel MRI sequences as neuromelanin-sensitive MRI are promising new tools to study nigrostriatal degeneration in vivo.

Major recent advances and previous data have led to a plausible model of how key proteins mediate neurotransmitter release. In this model, the soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins syntaxin-1, SNAP-25, and synaptobrevin form tight complexes that bring the membranes together and are crucial for membrane fusion. NSF and SNAPs disassemble SNARE complexes and ensure that fusion occurs through an exquisitely regulated pathway that starts with Munc18-1 bound to a closed conformation of syntaxin-1. Munc18-1 also binds to synaptobrevin, forming a template to assemble the SNARE complex when Munc13-1 opens syntaxin-1 while bridging the vesicle and plasma membranes. Synaptotagmin-1 and complexin bind to partially assembled SNARE complexes, likely stabilizing them and preventing fusion until Ca2+ binding to synaptotagmin-1 causes dissociation from the SNARE complex and induces interactions with phospholipids that help trigger release. Although fundamental questions remain about the mechanism of membrane fusion, these advances provide a framework to investigate the mechanisms underlying presynaptic plasticity.

Synaptic and cognitive deficits mediated by a severe reduction in excitatory neurotransmission caused by a disproportionate accumulation of the neuronal protein tau in dendritic spines is a fundamental mechanism that has been found repeatedly in models of tauopathies, including Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, and traumatic brain injury. Synapses thus damaged may contribute to dementia, among the most feared cause of debilitation in the elderly, and currently there are no treatments to repair them. Caspase-2 (Casp2) is an essential component of this pathological cascade. Although it is believed that Casp2 exerts its effects by hydrolyzing tau at aspartate-314, forming Δtau314, it is also possible that a non-catalytic mechanism is involved, since catalytically dead Casp2 is biologically active in at least one relevant cellular pathway, i.e., autophagy. To decipher whether the pathological effects of Casp2 on synaptic function are due to its catalytic or non-catalytic properties, we discovered and characterized a new Casp2 inhibitor, compound 1 (pK(i) (Casp2) = 8.12), which is 123-fold selective versus Casp3 and >2000-fold selective versus Casp1, Casp6, Casp7, and Casp9. In an in vitro assay based on Casp2-mediated cleavage of tau, compound 1 blocked the production of Δtau314. Importantly, compound 1 prevented tau from accumulating excessively in dendritic spines and rescued excitatory neurotransmission in cultured primary rat hippocampal neurons expressing the P301S tau variant linked to FTDP-17, a familial tauopathy. These results support the further development of small molecule Casp2 inhibitors to treat synaptic deficits in tauopathies.

Connectome mapping studies have documented a principal primary-to-transmodal gradient in the adult brain network, capturing a functional spectrum that ranges from perception and action to abstract cognition. However, how this gradient pattern develops and whether its development is linked to cognitive growth, topological reorganization, and gene expression profiles remain largely unknown. Using longitudinal resting-state functional magnetic resonance imaging data from 305 children (aged 6-14 years), we describe substantial changes in the primary-to-transmodal gradient between childhood and adolescence, including emergence as the principal gradient, expansion of global topography, and focal tuning in primary and default-mode regions. These gradient changes are mediated by developmental changes in network integration and segregation, and are associated with abstract processing functions such as working memory and expression levels of calcium ion regulated exocytosis and synaptic transmission-related genes. Our findings have implications for understanding connectome maturation principles in normal development and developmental disorders.

Sound localization involves information analysis in the lateral superior olive (LSO), a conspicuous nucleus in the mammalian auditory brainstem. LSO neurons weigh interaural level differences (ILDs) through precise integration of glutamatergic excitation from the cochlear nucleus (CN) and glycinergic inhibition from the medial nucleus of the trapezoid body (MNTB). Sound sources can be localized even during sustained perception, an accomplishment that requires robust neurotransmission. Virtually nothing is known about the sustained performance and the temporal precision of MNTB-LSO inputs after postnatal day (P)12 (time of hearing onset) and whether acoustic experience guides development. Here we performed whole-cell patch-clamp recordings to investigate neurotransmission of single MNTB-LSO fibres upon sustained electrical stimulation (1-200 Hz/60 s) at P11 and P38 in wild-type (WT) and deaf otoferlin (Otof) knock-out (KO) mice. At P11, WT and KO inputs performed remarkably similarly. In WTs, the performance increased drastically between P11 and P38, e.g. manifested by an 8 to 11-fold higher replenishment rate (RR) of synaptic vesicles and action potential robustness. Together, these changes resulted in reliable and highly precise neurotransmission at frequencies ≤100 Hz. In contrast, KO inputs performed similarly at both ages, implying impaired synaptic maturation. Computational modelling confirmed the empirical observations and established a reduced RR per release site for P38 KOs. In conclusion, acoustic experience appears to contribute massively to the development of reliable neurotransmission, thereby forming the basis for effective ILD detection. Collectively, our results provide novel insights into experience-dependent maturation of inhibitory neurotransmission and auditory circuits at the synaptic level. KEY POINTS: Inhibitory glycinergic inputs from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) are involved in sound localization. This brainstem circuit performs reliably throughout life. How such reliability develops is unknown. Here we investigated the role of acoustic experience on the functional maturation of MNTB-LSO inputs at juvenile (postnatal day P11) and young adult ages (P38) employing deaf mice lacking otoferlin (KO). We analysed neurotransmission at single MNTB-LSO fibres in acute brainstem slices employing prolonged high-frequency stimulation (1-200 Hz/60 s). At P11, KO inputs still performed normally, as manifested by normal synaptic attenuation, fidelity, replenishment rate, temporal precision and action potential robustness. Between P11 and P38, several synaptic parameters increased substantially in wild-type mice, collectively resulting in high-fidelity and temporally precise neurotransmission. In contrast, maturation of synaptic fidelity was largely absent in KOs after P11. Collectively, reliable neurotransmission at inhibitory MNTB-LSO inputs develops under the guidance of acoustic experience.