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In addition to its role as a neuronal energy substrate and signaling molecule involved in synaptic plasticity and memory consolidation, recent evidence shows that lactate produces antidepressant effects in animal models. However, the mechanisms underpinning lactate’s antidepressant actions remain largely unknown. In this study, we report that lactate reverses the effects of corticosterone on depressive-like behavior, as well as on the inhibition of both the survival and proliferation of new neurons in the adult hippocampus. Furthermore, the inhibition of adult hippocampal neurogenesis prevents the antidepressant-like effects of lactate. Pyruvate, the oxidized form of lactate, did not mimic the effects of lactate on adult hippocampal neurogenesis and depression-like behavior. Finally, our data suggest that conversion of lactate to pyruvate with the concomitant production of NADH is necessary for the neurogenic and antidepressant effects of lactate.

Background: Studies addressing the training-induced neuroplasticity and interrelationships of the lip, masseter, and tongue motor representations in the human motor cortex using single syllable repetition are lacking. Objective: This study investigated the impact of a repeated training in a novel PaTaKa diadochokinetic (DDK) orofacial motor task (OMT) on corticomotor control of the lips, masseter, and tongue muscles in young healthy participants. Methods: A total of 22 young healthy volunteers performed 3 consecutive days of training in an OMT. Transcranial magnetic stimulation was applied to elicit motor evoked potentials (MEPs) from the lip, masseter, tongue, and first dorsal interosseous (FDI, internal control) muscles. MEPs were assessed by stimulus–response curves and corticomotor mapping at baseline and after OMT. The DDK rate from PaTaKa single syllable repetition and numeric rating scale (NRS) scores were also obtained at baseline and immediately after each OMT. Repeated-measures analysis of variance was used to detect differences at a significance level of 5%. Results: There was a significant effect of OMT and stimulus intensity on the lips, masseter, and tongue MEPs compared to baseline (p .05). OMT increased corticomotor topographic maps area (p

Long-term depression (LTD) of synaptic strength can take multiple forms and contribute to circuit remodeling, memory encoding or erasure. The generic term LTD encompasses various induction pathways, including activation of NMDA, mGlu or P2X receptors. However, the associated specific molecular mechanisms and effects on synaptic physiology are still unclear. We here compare how NMDAR- or P2XR-dependent LTD affect synaptic nanoscale organization and function in rodents. While both LTDs are associated with a loss and reorganization of synaptic AMPARs, only NMDAR-dependent LTD induction triggers a profound reorganization of PSD-95. This modification, which requires the autophagy machinery to remove the T19-phosphorylated form of PSD-95 from synapses, leads to an increase in AMPAR surface mobility. We demonstrate that these post-synaptic changes that occur specifically during NMDAR-dependent LTD result in an increased short-term plasticity improving neuronal responsiveness of depressed synapses. Our results establish that P2XR- and NMDAR-mediated LTD are associated to functionally distinct forms of LTD., Long-term depression (LTD) of synaptic strength contributes to circuit remodeling, memory encoding and erasure. Here, the authors show that P2XR- and NMDAR-dependent LTD are associated with distinct and precise molecular modifications that lead to specific modification of synapse function.

Dopamine-dependent long-term plasticity is believed to be a cellular mechanism underlying reinforcement learning. In response to reward and reward-predicting cues, phasic dopamine activity potentiates the efficacy of corticostriatal synapses on spiny projection neurons (SPNs). Since phasic dopamine activity also encodes other behavioural variables, it is unclear how postsynaptic neurons identify which dopamine event is to induce long-term plasticity. Additionally, it is unknown how phasic dopamine released from arborised axons can potentiate targeted striatal synapses through volume transmission. To examine these questions we manipulated striatal cholinergic interneurons (ChIs) and dopamine neurons independently in two distinct in vivo paradigms. We report that long-term potentiation (LTP) at corticostriatal synapses with SPNs is dependent on the coincidence of pauses in ChIs and phasic dopamine activation, critically accompanied by SPN depolarisation. Thus, the ChI pause defines the time window for phasic dopamine to induce plasticity, while depolarisation of SPNs constrains the synapses eligible for plasticity.

Cerebral palsy (CP) is predominantly a disorder of movement, with evidence of sensory-motor dysfunction. CIMT1 is a widely used treatment for hemiplegic CP. However, effects of CIMT on somatosensory processing remain unclear. To examine potential CIMT-induced changes in cortical tactile processing, we designed a prospective study, during which 10 children with hemiplegic CP (5 to 8 years old) underwent an intensive one-week-long nonremovable hard-constraint CIMT. Before and directly after the treatment, we recorded their cortical event-related potential (ERP) responses to calibrated light touch (versus a control stimulus) at the more and less affected hand. To provide insights into the core neurophysiological deficits in light touch processing in CP as well as into the plasticity of this function following CIMT, we analyzed the ERPs within an electrical neuroimaging framework. After CIMT, brain areas governing the more affected hand responded to touch in configurations similar to those activated by the hemisphere controlling the less affected hand before CIMT. This was in contrast to the affected hand where configurations resembled those of the more affected hand before CIMT. Furthermore, dysfunctional patterns of brain activity, identified using hierarchical ERP cluster analyses, appeared reduced after CIMT in proportion with changes in sensory-motor measures (grip or pinch movements). These novel results suggest recovery of functional sensory activation as one possible mechanism underlying the effectiveness of intensive constraint-based therapy on motor functions in the more affected upper extremity in CP. However, maladaptive effects on the less affected constrained extremity may also have occurred. Our findings also highlight the use of electrical neuroimaging as feasible methodology to measure changes in tactile function after treatment even in young children, as it does not require active participation.

Heart-rate estimation is a fundamental feature of modern wearable devices. In this paper we propose a machine intelligent approach for heart-rate estimation from electrocardiogram (ECG) data collected using wearable devices. The novelty of our approach lies in (1) encoding spatio-temporal properties of ECG signals directly into spike train and using this to excite recurrently connected spiking neurons in a Liquid State Machine computation model; (2) a novel learning algorithm; and (3) an intelligently designed unsupervised readout based on Fuzzy c-Means clustering of spike responses from a subset of neurons (Liquid states), selected using particle swarm optimization. Our approach differs from existing works by learning directly from ECG signals (allowing personalization), without requiring costly data annotations. Additionally, our approach can be easily implemented on state-of-the-art spiking-based neuromorphic systems, offering high accuracy, yet significantly low energy footprint, leading to an extended battery life of wearable devices. We validated our approach with CARLsim, a GPU accelerated spiking neural network simulator modeling Izhikevich spiking neurons with Spike Timing Dependent Plasticity (STDP) and homeostatic scaling. A range of subjects are considered from in-house clinical trials and public ECG databases. Results show high accuracy and low energy footprint in heart-rate estimation across subjects with and without cardiac irregularities, signifying the strong potential of this approach to be integrated in future wearable devices., Comment: 51 pages, 12 figures, 6 tables, 95 references. Under submission at Elsevier Neural Networks

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Kainate receptors (KARs) are glutamate-gated ion channels that play fundamental roles in regulating neuronal excitability and network function in the brain. After being cloned in the 1990s, important progress has been made in understanding the mechanisms controlling the molecular and cellular properties of KARs, and the nature and extent of their regulation of wider neuronal activity. However, there have been significant recent advances towards understanding KAR trafficking through the secretory pathway, their precise synaptic positioning, and their roles in synaptic plasticity and disease. Here we provide an overview highlighting these new findings about the mechanisms controlling KARs and how KARs, in turn, regulate other proteins and pathways to influence synaptic function.

Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer's disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Understanding the emerging roles of astrocytes in cognitive function and dysfunction will open up a large array of new therapeutic opportunities.

The mammalian brain is composed of densely connected and interacting regions, which form structural and functional networks. An improved understanding of the structure–function relation is crucial to understand the structural underpinnings of brain function and brain plasticity after injury. It is currently unclear how functional connectivity strength relates to structural connectivity strength. We obtained an overview of recent papers that report on correspondences between quantitative functional and structural connectivity measures in the mammalian brain. We included network studies in which functional connectivity was measured with resting-state fMRI, and structural connectivity with either diffusion-weighted MRI or neuronal tract tracers. Twenty-seven of the 28 included studies showed a positive structure–function relationship. Large inter-study variations were found comparing functional connectivity strength with either quantitative diffusion-based (correlation coefficient (r) ranges: 0.18–0.82) or neuronal tracer-based structural connectivity measures (r = 0.24–0.74). Two functional datasets demonstrated lower structure–function correlations with neuronal tracer-based (r = 0.22 and r = 0.30) than with diffusion-based measures (r = 0.49 and r = 0.65). The robust positive quantitative structure–function relationship supports the hypothesis that structural connectivity provides the hardware from which functional connectivity emerges. However, methodological differences between the included studies complicate the comparison across studies, which emphasize the need for validation and standardization in brain structure–function studies.

Objective: Electroconvulsive therapy (ECT) is still the most effective treatment of severe and therapy-refractory major depressive disorder. Cognitive side effects are the major disadvantage of ECT. Cognitive deficits are generally temporary in nature and may be mediated by the hippocampus. Recent studies have shown a temporary increase in hippocampal volume and a temporary decrease in cognitive functioning post-ECT compared with pre-ECT. This study investigates whether these volumetric changes are related to changes in cognitive functioning after ECT.Methods: Nineteen medication-free patients with treatment-resistant major depressive disorder underwent a whole-brain magnetic resonance imaging scan and a neuropsychological examination (including the Rey auditory verbal learning task, Wechsler Memory Scale Visual Reproduction, fluency, Trail Making Task) within 1 week before and within 1 week after the course of ECT. Electroconvulsive therapy was administered twice a week bitemporally with a brief pulse. A matched healthy control group (n = 18) received the same neuropsychological examination and at a similar interval to that of the patients.Results: Hippocampal volumes increased significantly from pretreatment to posttreatment in patients. Mean performance on cognitive tasks declined, or remained stable, whereas performance in controls generally improved because of retesting effects. The increase in hippocampal volume was related to changes in cognitive performance, indicating that this increase co-occurred with a decrease in cognitive functioning.Conclusions: Our findings tentatively suggest that the temporal increase in hippocampal volume after treatment, which may result from neurotrophic processes and is thought to be crucial for the antidepressive effect, is also related to the temporary cognitive side effects of ECT.

Summary Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression—pre- or postsynaptic—is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity., Highlights • A theory of synaptic plasticity that predicts pre- and postsynaptic expression loci • The framework captures LTP and LTD data across different experiments and brain regions • Variability of pre/post changes due to optimizing postsynaptic response statistics • Optimization at inhibitory synapses suggests a statistically optimal E/I balance, For decades the variability in expression loci of long-term synaptic plasticity has remained enigmatic. Costa et al. propose a theory in which this variability is a consequence of postsynaptic response optimization, consistent with a wide range of experimental observations.

MCT2 is the main neuronal monocarboxylate transporter needed by neurons if they are to use lactate as an additional energy substrate. Previous evidence suggested that some MCT2 could be located in postsynaptic elements of glutamatergic synapses. Using post-embedding electron microscopic immunocytochemistry, it is demonstrated that MCT2 is present at postsynaptic density of asymmetric synapses, in the stratum radiatum of both rat hippocampal CA1 and CA3 regions, as well as at parallel fibre-Purkinje cell synapses in mouse cerebellum. MCT2 levels were significantly lower at mossy fibre synapses on CA3 neurons, and MCT2 was almost absent from symmetric synapses on CA1 pyramidal cells. It could also be demonstrated using quantitative double-labeling immunogold cytochemistry that MCT2 and AMPA receptor GluR2/3 subunits have a similar postsynaptic distribution at asymmetric synapses with high levels expressed within the postsynaptic density. In addition, as for AMPA receptors, a significant proportion of MCT2 is located on vesicular membranes within the postsynaptic spine, forming an intracellular pool available for a putative postsynaptic endo/exocytotic trafficking at these excitatory synapses. Altogether, the data presented provide evidence for MCT2 expression in the postsynaptic density area at specific subsets of glutamatergic synapses, and also suggest that MCT2, like AMPA receptors, could undergo membrane trafficking.

Postnatal hippocampal neurogenesis induces network remodeling and may participate to mechanisms of learning. In turn, the maturation and survival of newborn neurons is regulated by their activity. Here, we tested the effect of a cell-autonomous overexpression of synaptic adhesion molecules on the maturation and survival of neurons born postnatally and on hippocampal-dependent memory performances. Families of adhesion molecules are known to induce pre- and post-synaptic assembly. Using viral targeting, we overexpressed three different synaptic adhesion molecules, SynCAM1, Neuroligin-1B and Neuroligin-2A in newborn neurons in the dentate gyrus of 7- to 9-week-old mice. We found that SynCAM1 increased the morphological maturation of dendritic spines and mossy fiber terminals while Neuroligin-1B increased spine density. In contrast, Neuroligin-2A increased both spine density and size as well as GABAergic innervation and resulted in a drastic increase of neuronal survival. Surprisingly, despite increased neurogenesis, mice overexpressing Neuroligin-2A in new neurons showed decreased memory performances in a Morris water maze task. These results indicate that the cell-autonomous overexpression of synaptic adhesion molecules can enhance different aspects of synapse formation on new neurons and increase their survival. Furthermore, they suggest that the mechanisms by which new neurons integrate in the postnatal hippocampus conditions their functional implication in learning and memory.

Synaptic rearrangements during critical periods of postnatal brain development rely on the correct formation, strengthening, and elimination of synapses and associated dendritic spines to form functional networks. The correct balance of these processes is thought to be regulated by synapse-specific changes in the subunit composition of NMDA-type glutamate receptors (NMDARs). Among these, the nonconventional NMDAR subunit GluN3A has been suggested to play a role as a molecular brake in synaptic maturation. We tested here this hypothesis using confocal time-lapse imaging in rat hippocampal organotypic slices and assessed the role of GluN3A-containing NMDARs on spine dynamics. We found that overexpressing GluN3A reduced spine density over time, increased spine elimination, and decreased spine stability. The effect of GluN3A overexpression could be further enhanced by using an endocytosis-deficient GluN3A mutant and reproduced by silencing the adaptor protein PACSIN1, which prevents the endocytosis of endogenous GluN3A. Conversely, silencing of GluN3A reduced spine elimination and favored spine stability. Moreover, reexpression of GluN3A in more mature tissue reinstated an increased spine pruning and a low spine stability. Mechanistically, the decreased stability in GluN3A overexpressing neurons could be linked to a failure of plasticity-inducing protocols to selectively stabilize spines and was dependent on the ability of GluN3A to bind the postsynaptic scaffold GIT1. Together, these data provide strong evidence that GluN3A prevents the activity-dependent stabilization of synapses thereby promoting spine pruning, and suggest that GluN3A expression operates as a molecular signal for controlling the extent and timing of synapse maturation.

INTRODUCTION Inhibitory control refers to our ability to suppress ongoing motor affective or cognitive processes and mostly depends on a fronto basal brain network. Inhibitory control deficits participate in the emergence of several prominent psychiatric conditions including attention deficit/hyperactivity disorder or addiction. The rehabilitation of these pathologies might therefore benefit from training based behavioral interventions aiming at improving inhibitory control proficiency and normalizing the underlying neurophysiological mechanisms. The development of an efficient inhibitory control training regimen first requires determining the effects of practicing inhibition tasks. METHODS We addressed this question by contrasting behavioral performance and electrical neuroimaging analyses of event related potentials (ERPs) recorded from humans at the beginning versus the end of 1 h of practice on a stop signal task (SST) involving the withholding of responses when a stop signal was presented during a speeded auditory discrimination task. RESULTS Practicing a short SST improved behavioral performance. Electrophysiologically ERPs differed topographically at 200 msec post stimulus onset indicative of the engagement of distinct brain network with learning. Source estimations localized this effect within the inferior frontal gyrus the pre supplementary motor area and the basal ganglia. CONCLUSION Our collective results indicate that behavioral and brain responses during an inhibitory control task are subject to fast plastic changes and provide evidence that high order fronto basal executive networks can be modified by practicing a SST.

Lysosomes have traditionally been viewed as degradative organelles, although a growing body of evidence suggests that they can function as Ca2+ stores. Here we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca2+ release from lysosomes in the dendrites. This Ca2+ release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca2+ signaling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long-term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling.

The Morris water maze (MWM) spatial learning task has been demonstrated to involve a cognitive switch of action control to serve the transition from an early towards a late learning phase. However, the molecular mechanisms governing this switch are largely unknown. We employed MALDI MS imaging (MSI) to screen for changes in expression of small proteins in brain structures implicated in the different learning phases. We compared mice trained for 3days and 30days in the MWM, reflecting an early and a late learning phase in relation to the acquisition of a spatial learning task. An ion with m/z of 6724, identified as PEP-19/pcp4 by top-down tandem MS, was detected at higher intensity in the dorsal striatum of the late learning phase group compared with the early learning phase group. In addition, mass spectrometric analysis of synaptosomes confirmed the presence of PEP-19/pcp4 at the synapse. PEP-19/pcp4 has previously been identified as a critical determinant of synaptic plasticity in locomotor learning. Our findings extend PEP-19/pcp4 function to spatial learning in the forebrain and put MSI forward as a valid and unbiased research strategy for the discovery and identification of the molecular machinery involved in learning, memory and synaptic plasticity. publisher: Elsevier articletitle: MS imaging and mass spectrometric synaptosome profiling identify PEP-19/pcp4 as a synaptic molecule involved in spatial learning in mice journaltitle: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics articlelink: http://dx.doi.org/10.1016/j.bbapap.2016.10.007 content_type: article copyright: © 2016 Elsevier B.V. All rights reserved. ispartof: Biochimica et Biophysica Acta vol:1865 issue:7 pages:936-945 ispartof: location:Netherlands status: published

Presynaptic kainate receptors (KARs) modulate transmission between dentate granule cells and CA3 pyramidal neurons. Whether presynaptic KARs affect other synapses made by granule cell axons [mossy fibers (MFs)], on hilar mossy cells or interneurons, is not known. Nor is it known whether glutamate release from a single MF is sufficient to activate these receptors. Here, we monitor Ca2+in identified MF boutons traced from granule cell bodies. We show that a single action potential in a single MF activates both presynaptic KARs and Ca2+stores, contributing to use-dependent facilitation at MF–CA3 pyramidal cell synapses. Rapid local application of kainate to the giant MF bouton has no detectable effect on the resting Ca2+but facilitates action-potential-evoked Ca2+entry through a Ca2+store-dependent mechanism. Localized two-photon uncaging of the Ca2+store receptor ligand IP3directly confirms the presence of functional Ca2+stores at these boutons. In contrast, presynaptic Ca2+kinetics at MF synapses on interneurons or mossy cells are insensitive to KAR blockade, to local kainate application or to photolytic release of IP3. Consistent with this, postsynaptic responses evoked by activation of a single MF show KAR-dependent paired-pulse facilitation in CA3 pyramidal cells, but not in interneurons or mossy cells. Thus, KAR–Ca2+store coupling acts as a synapse-specific, short-range autoreceptor mechanism.

In natural settings the same sound source is often heard repeatedly, with variations in spectro-temporal and spatial characteristics. We investigated how such repetitions influence sound representations and in particular how auditory cortices keep track of recently vs. often heard objects. A set of 40 environmental sounds was presented twice, i.e. as prime and as repeat, while subjects categorized the corresponding sound sources as living vs. non-living. Electrical neuroimaging analyses were applied to auditory evoked potentials (AEPs) comparing primes vs. repeats (effect of presentation) and the four experimental sections. Dynamic analysis of distributed source estimations revealed i) a significant main effect of presentation within the left temporal convexity at 164–215 ms post-stimulus onset; and ii) a significant main effect of section in the right temporo-parietal junction at 166–213 ms. A 3-way repeated measures ANOVA (hemisphere × presentation × section) applied to neural activity of the above clusters during the common time window confirmed the specificity of the left hemisphere for the effect of presentation, but not that of the right hemisphere for the effect of section. In conclusion, spatio-temporal dynamics of neural activity encode the temporal history of exposure to sound objects. Rapidly occurring plastic changes within the semantic representations of the left hemisphere keep track of objects heard a few seconds before, independent of the more general sound exposure history. Progressively occurring and more long-lasting plastic changes occurring predominantly within right hemispheric networks, which are known to code for perceptual, semantic and spatial aspects of sound objects, keep track of multiple exposures.

Recent studies have provided long sought evidence that behavioural learning involves specific synapse gain and elimination processes which lead to memory traces that influence behaviour. The connectivity rearrangements are preceded by enhanced synapse turnover which can be modulated through changes in inhibitory connectivity. Behaviourally related synapse rearrangement events tend to co occur spatially within short stretches of dendrites and involve signalling pathways partially overlapping with those controlling the functional plasticity of synapses. The new findings suggest that a mechanistic understanding of learning and memory processes will require monitoring ensembles of synapses in situ and the development of synaptic network models that combine changes in synaptic function and connectivity. © 2012 Macmillan Publishers Limited. All rights reserved.

Synaptic activity, such as long-term potentiation (LTP), has been shown to induce morphological plasticity of excitatory synapses on dendritic spines through the spine head and postsynaptic density (PSD) enlargement and reorganization. Much less, however, is known about activity-induced morphological modifications of inhibitory synapses. Using an in vitro model of rat organotypic hippocampal slice cultures and electron microscopy, we studied activity-related morphological changes of somatic inhibitory inputs triggered by a brief oxygen-glucose deprivation (OGD) episode, a condition associated with a synaptic enhancement referred to as anoxic LTP and a structural remodeling of excitatory synapses. Three-dimensional reconstruction of inhibitory axo-somatic synapses at different times before and after brief OGD revealed important morphological changes. The PSD area significantly and markedly increased at synapses with large and complex PSDs, but not at synapses with simple, macular PSDs. Activity-related changes of PSD size and presynaptic bouton volume developed in a strongly correlated manner. Analyses of single and serial sections further showed that the density of inhibitory synaptic contacts on the cell soma did not change within 1 h after OGD. In contrast, the proportion of the cell surface covered with inhibitory PSDs, as well as the complexity of these PSDs significantly increased, with less macular PSDs and more complex, segmented shapes. Together, these data reveal a rapid activity-related restructuring of somatic inhibitory synapses characterized by an enlargement and increased complexity of inhibitory PSDs, providing a new mechanism for a quick adjustment of the excitatory-inhibitory balance. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.

Background. Stroke is the leading cause of adult disability, but treatment options remain limited, leaving most patients with incomplete recovery. Patient and animal studies have shown potential of noninvasive brain stimulation (NIBS) strategies to improve function after stroke. However, mechanisms underlying therapeutic effects of NIBS are unclear and there is no consensus on which NIBS protocols are most effective. Objective. Provide a review of articles that assessed effects and mechanisms of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) in animal stroke models. Methods. Articles were searched in PubMed, including cross-references. Results. Nineteen eligible studies reporting effects of rTMS or tDCS after stroke in small rodents were identified. Seventeen of those described improved functional recovery or neuroprotection compared with untreated control or sham-stimulated groups. The effects of rTMS could be related to molecular mechanisms associated with ischemic tolerance, neuroprotection, anti-apoptosis, neurogenesis, angiogenesis, or neuroplasticity. Favorable outcome appeared most effectively when using high-frequency (>5 Hz) rTMS or intermittent theta burst stimulation of the ipsilesional hemisphere. tDCS effects were strongly dependent on stimulation polarity and onset time. Although these findings are promising, most studies did not meet Good Laboratory Practice assessment criteria. Conclusions. Despite limited data availability, animal stroke model studies demonstrate potential of NIBS to promote stroke recovery through different working mechanisms. Future studies in animal stroke models should adhere to Good Laboratory Practice guidelines and aim to further develop clinically applicable treatment protocols by identifying most favorable stimulation parameters, treatment onset, adjuvant therapies, and underlying modes of action.

International audience; Presenilin 1 (PS1) mutations are responsible for a majority of early onset familial Alzheimer's disease (FAD) cases, in part by increasing the production of Abeta peptides. However, emerging evidence suggests other possible effects of PS1 on synaptic dysfunction where PS1 might contribute to the pathology independent of Abeta. We chose to study the L286V mutation, an aggressive FAD mutation which has never been analyzed at the electrophysiological and morphological levels. In addition, we analyzed for the first time the long term effects of wild-type human PS1 overexpression. We investigated the consequences of the overexpression of either wild-type human PS1 (hPS1) or the L286V mutated PS1 variant (mutPS1) on synaptic functions by analyzing synaptic plasticity and associated spine density changes from 3 to 15 months of age. We found that mutPS1 induces a transient increase observed only in 4- to 5-month-old mutPS1 animals in NMDA receptor (NMDA-R)-mediated responses and LTP compared with hPS1 mice and nontransgenic littermates. The increase in synaptic functions is concomitant with an increase in spine density. With increasing age, however, we found that the overexpression of human wild-type PS1 progressively decreased NMDA-R-mediated synaptic transmission and LTP, without neurodegeneration. These results identify for the first time a transient increase in synaptic function associated with L286V mutated PS1 variant in an age-dependent manner. In addition, they support the view that the PS1 overexpression promotes synaptic dysfunction in an Abeta-independent manner and underline the crucial role of PS1 during both normal and pathological aging.

Mice actively explore their environment by rhythmically sweeping their whiskers. As a consequence, neuronal activity in somatosensory pathways is modulated by the frequency of whisker movement. The potential role of rhythmic neuronal activity for the integration and consolidation of sensory signals, however, remains unexplored. Here, we show that a brief period of rhythmic whisker stimulation in anesthetized mice resulted in a frequency-specific long-lasting increase in the amplitude of somatosensory-evoked potentials in the contralateral primary somatosensory (barrel) cortex. Mapping of evoked potentials and intracortical recordings revealed that, in addition to potentiation in layers IV and II/III of the barrel cortex, rhythmic whisker stimulation induced a decrease of somatosensory-evoked responses in the supragranular layers of the motor cortex. To assess whether rhythmic sensory input-based plasticity might arise in natural settings, we exposed mice to environmental enrichment. We found that it resulted in somatosensory-evoked responses of increased amplitude, highlighting the influence of previous sensory experience in shaping sensory responses. Importantly, environmental enrichment-induced plasticity occluded further potentiation by rhythmic stimulation, indicating that both phenomena share common mechanisms. Overall, our results suggest that natural, rhythmic patterns of whisker activity can modify the cerebral processing of sensory information, providing a possible mechanism for learning during sensory perception.

Axon guidance and target-derived signals control axonal behavior by regulating the cytoskeleton through poorly defined mechanisms. In particular, how these signaling molecules regulate the growth and directionality of microtubules is not well understood. Here we examine the effect of Wnts on growth cone remodeling, a process that precedes synapse formation. Time-lapse recordings reveal that Wnt3a rapidly inhibits growth cone translocation while inducing growth cone enlargement. These changes in axonal behavior are associated with changes in the organization of microtubules. Time-lapse imaging of EB3-GFP (green fluorescent protein)-labeled microtubule plus-ends demonstrates that Wnt3a regulates microtubule directionality, resulting in microtubule looping, growth cone pausing, and remodeling. Analyses of Dishevelled-1 (Dvl1) mutant neurons demonstrate that Dvl1 is required for Wnt-mediated microtubule reorganization and axon remodeling. Wnt signaling directly affects the microtubule cytoskeleton by unexpectedly inducing adenomatous polyposis coli (APC) loss from microtubule plus-ends. Consistently, short hairpin RNA knockdown of APC mimics Wnt3a function. Together, our findings define APC as a key Wnt signaling target in the regulation of microtubule growth direction.

Human beings have an amazing capacity to learn new skills and adapt to new environments. However, several obstacles remain to be overcome in designing paradigms to broadly improve quality of life. Arguably, the most notable impediment to this goal is that learning tends to be quite specific to the trained regimen and does not transfer to even qualitatively similar tasks. This severely limits the potential benefits of learning to daily life. This review discusses training regimens that lead to the acquisition of new knowledge and strategies that can be used flexibly across a range of tasks and contexts. Possible characteristics of training regimens are proposed that may be responsible for augmented learning, including the manner in which task difficulty is progressed, the motivational state of the learner, and the type of feedback the training provides. When maximally implemented in rehabilitative paradigms, these characteristics may greatly increase the efficacy of training.

Psychophysical and neuroimaging studies suggest that perceptual learning may affect activity in primary visual cortex (V1). Yet, it remains unclear whether such changes involve intrinsic V1 plasticity or feedback from later processing stages. Here we recorded high-density electro-encephalography in 24 volunteers, 24-h after training on a visual texture discrimination task in the upper or lower visual-field. Post-training improvement in upper visual-field was associated with changes in early visual responses, starting 40ms post-stimulus, with reduced amplitude of retinotopic C1, known to reflect V1 activity. No behavioral or neurophysiological effect was found after training in lower visual-field, suggesting retinotopic constraints on perceptual learning. Our results demonstrate that successful acquisition of a perceptual skill can produce long-lasting changes for initial sensory inputs in the adult human visual system.

The brain evolved cellular mechanisms for adapting synaptic function to energy supply. This is particularly evident when homeostasis is challenged by stress. Signaling loops between the mitochondria and synapses scale neuronal connectivity with bioenergetics capacity. A biphasic “inverted U shape” response to the stress hormone glucocorticoids is demonstrated in mitochondria and at synapses, modulating neural plasticity and physiological responses. Low dose enhances neurotransmission, synaptic growth, mitochondrial functions, learning, and memory whereas chronic, higher doses produce inhibition of these functions. The range of physiological effects by stress and glucocorticoid depends on the dose, duration, and context at exposure. These criteria are met by neuronal activity and the circadian, stress-sensitive and ultradian, stress-insensitive modes of glucocorticoid secretion. A major hallmark of stress-related neuropsychiatric disorders is the disrupted glucocorticoid rhythms and tissue resistance to signaling with the glucocorticoid receptor (GR). GR resistance could result from the loss of context-dependent glucocorticoid signaling mediated by the downregulation of the activity-dependent neurotrophin BDNF. The coincidence of BDNF and GR signaling changes glucocorticoid signaling output with consequences on mitochondrial respiration efficiency, synaptic plasticity, and adaptive trajectories.

Long-term consolidation of memories depends on processes occurring many hours after acquisition. Whether this involves plasticity that is specifically required for long-term consolidation remains unclear. We found that learning-induced plasticity of local parvalbumin (PV) basket cells was specifically required for long-term, but not short/intermediate-term, memory consolidation in mice. PV plasticity, which involves changes in PV and GAD67 expression and connectivity onto PV neurons, was regulated by cAMP signaling in PV neurons. Following induction, PV plasticity depended on local D1/5 dopamine receptor signaling at 0-5 h to regulate its magnitude, and at 12-14 h for its continuance, ensuring memory consolidation. D1/5 dopamine receptor activation selectively induced DARPP-32 and ERK phosphorylation in PV neurons. At 12-14 h, PV plasticity was required for enhanced sharp-wave ripple densities and c-Fos expression in pyramidal neurons. Our results reveal general network mechanisms of long-term memory consolidation that requires plasticity of PV basket cells induced after acquisition and sustained subsequently through D1/5 receptor signaling.

The possibility that, following early auditory deprivation, the remaining senses such as vision are enhanced has been met with much excitement. However, deaf individuals exhibit both better and worse visual skills than hearing controls. We show that, when deafness is considered to the exclusion of other confounds, enhancements in visual cognition are noted. The changes are not, however, widespread but are selective, limited, as we propose, to those aspects of vision that are attentionally demanding and would normally benefit from auditory-visual convergence. The behavioral changes are accompanied by a reorganization of multisensory areas, ranging from higher-order cortex to early cortical areas, highlighting cross-modal interactions as a fundamental feature of brain organization and cognitive processing.

Numerous studies have shown the neuroprotective and regenerative benefits of glial cell line-derived neurotrophic factor (GDNF) in animal models of PD. Brain delivery of GDNF can, however, be associated with limiting side-effects in both primates and PD patients, rendering the duration of delivery a critical factor. In the present study, the effects of transient vs. sustained GDNF delivery by encapsulated cells were evaluated in a bilateral animal model, closely mimicking advanced PD. One week following bilateral striatal 6- hydroxydopamine injections in rats, capsules loaded with human fibroblasts genetically engineered to release GDNF were bilaterally implanted in the striatum. GDNF delivery resulted in a significant improvement of movement initiation and swimming performance in the lesioned animals, associated with striatal reinnervation of dopaminergic fibers. To test the sustainability of the behavioral improvement, GDNF-secreting capsules were withdrawn in a subgroup of animals, 7 weeks post-implantation. Strikingly, both the behavioral and morphological improvements were maintained until the sacrifice of the animals 6 weeks post-GDNF withdrawal. The sustained cellular and behavioral benefits after GDNF washout suggest the need for temporary delivery of the trophic factor in PD. Retrievable encapsulated cells represent an attractive delivery tool to achieve this purpose.

Relatively mild ischemic episode can initiate a chain of events resulting in delayed cell death and significant lesions in the affected brain regions. We studied early synaptic modifications after brief ischemia modeled in rats by transient vessels' occlusion in vivo or oxygen-glucose deprivation in vitro and resulting in delayed death of hippocampal CA1 pyramidal cells. Electron microscopic analysis of excitatory spine synapses in CA1 stratum radiatum revealed a rapid increase of the postsynaptic density (PSD) thickness and length, as well as formation of concave synapses with perforated PSD during the first 24 h after ischemic episode, followed at the long term by degeneration of 80% of synaptic contacts. In presynaptic terminals, ischemia induced a depletion of synaptic vesicles and changes in their spatial arrangement: they became more distant from active zones and had larger intervesicle spacing compared to controls. These rapid structural synaptic changes could be implicated in the mechanisms of cell death or adaptive plasticity. Comparison of the in vivo and in vitro model systems used in the study demonstrated a general similarity of these early morphological changes, confirming the validity of the in vitro model for studying synaptic structural plasticity.

The polysialylated neural cell adhesion molecule (PSA-NCAM) has been implicated in activity-dependent synaptic remodeling and memory formation. Here, we questioned whether training-induced modulation of PSA-NCAM expression might be related to individual differences in spatial learning abilities. At 12 h posttraining, immunohistochemical analyses revealed a learning-induced up-regulation of PSA-NCAM in the hippocampal dentate gyrus that was related to the spatial learning abilities displayed by rats during training. Specifically, a positive correlation was found between latency to find the platform and subsequent activated PSA levels, indicating that greater induction of polysialylation was observed in rats with the slower acquisition curve. At posttraining times when no learning-associated activation of PSA was observed, no such correlation was found. Further experiments revealed that performance in the massed water maze training is related to a pattern of spatial learning and memory abilities, and to learning-related glucocorticoid responsiveness. Taken together, our findings suggest that the learning-related neural circuits of fast learners are better suited to solving the water maze task than those of slow learners, the latter relying more on structural reorganization to form memory, rather than the relatively economic mechanism of altering synaptic efficacy that is likely used by the former.

The length of myelin sheaths affects conduction speed along axons and information propagation. It has recently become clear that myelin may be adaptively modified to modulate circuit function, implying that length remodeling of myelin sheaths should occur. However, direct evidence for such events is lacking. We have investigated how myelination patterns are formed, maintained, and remodeled using long-term imaging and myelin ablation in zebrafish. We demonstrate that length differences between myelin sheaths are established by rapid and variable growth within 3 days after their formation, independently of their time of formation, and even along discontinuously myelinated axons. Afterward, sheaths continue extending at similar rates to compensate for overall animal growth. In consequence, once axon myelination patterns are established, they are maintained over long periods of time. We tested whether mature myelin sheaths can remodel by removing individual sheaths from single axons by targeted ablation. Remarkably, extensive changes in sheath length and number occurred, which frequently restored the original myelination pattern. Our results show that axons can control myelin growth and remodeling, and we provide evidence for a homeostatic control of axon myelination patterns by maintenance and remodeling of myelin sheath length, with implications for circuit development, function, and repair.

The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger excitatory postsynaptic currents and increased spontaneous activity in vivo. Furthermore, BC1 KO mice have enlarged spine heads and postsynaptic densities and increased synaptic levels of glutamate receptors and PSD-95. Of note, BC1 KO mice show aberrant structural plasticity in response to whisker deprivation, impaired texture novel object recognition and altered social behavior. Thus, our study highlights a role for BC1 RNA in experience-dependent plasticity and learning in the mammalian adult neocortex, and provides insight into the function of brain ncRNAs regulating synaptic transmission, plasticity and behavior, with potential relevance in the context of intellectual disabilities and psychiatric disorders., Brain cytoplasmic (BC1) RNA is a non-coding RNA that has been implicated in translational regulation, seizure, and anxiety. Here, the authors show that in the cortex, BC1 RNA is required for sensory deprivation-induced structural plasticity of dendritic spines, as well as for correct sensory learning and social behaviors.

Risk for adult psychiatric disorders is partially determined by early-life alterations occurring during neural circuit formation and maturation. In this perspective, recent data show that the serotonin system regulates key cellular processes involved in the construction of cortical circuits. Translational data for rodents indicate that early-life serotonin dysregulation leads to a wide range of behavioral alterations, ranging from stress-related phenotypes to social deficits. Studies in humans have revealed that serotonin-related genetic variants interact with early-life stress to regulate stress-induced cortisol responsiveness and activate the neural circuits involved in mood and anxiety disorders. Emerging data demonstrate that early-life adversity induces epigenetic modifications in serotonin-related genes. Finally, recent findings reveal that selective serotonin reuptake inhibitors can reinstate juvenile-like forms of neural plasticity, thus allowing the erasure of long-lasting fear memories. These approaches are providing new insights on the biological mechanisms and clinical application of antidepressants.El riesgo para los trasiornos psiquiátricos del adulto está determinado en parte por alteraciones de los primeros años de vida que ocurren durante la formatión y maduración de los circuitos neurales. Desde esta perspectiva, hay información reciente que muestra que el sistema serotoninérgico regula los procesos celulares que particípan en la construcción de los circuitos corticales. Hay información traslacional de roedores que indica que la falta de regulación de serotonina en etapas precoces de la vida conduce a una amplía gama de alteraciones conductuales, que van desde fenotipos relacionados con el estrés a déficits sociales. Los estudios en humanos han revelado que las variantes genéticas relacionadas con la serotonina interactúan con el estrés de los primeros años para regular la respuesta de cortisol inducida por el estrés y activar los circuitos neurales involucrados en los trastornos del ánimo y de ansiedad. Han aparecido daios que demuestran que la adversidad en los primeros años de vida induce modificaciones epigenéticas en los genes relacionados con la serotonina. Finalmente, hay hallazgos recientes que revelan que los inhibidores selectivos de la recaptura de serotonina pueden restituir formas de tipo juvenil de plastícidad neural, lo que permite la supresión de memorias de temor de larga duración. Estas aproximaciones están aportando nuevas perspectivas acerca de los mecanismos biológicos y la aplicación clínica de los antidepresivos.Le risque de développer des maladies psychiatriques à l'âge adulte est en partie déterminé par des altérations précoces touchant la formation et la maturation des circuits neuronaux. Dans cette perspective, des données récentes indiquent que le système sérotoninergique régule des événements cellulaires impliqués dans la construction des circuits corticaux. Des recherches translationnelles chez l'animal révèlent qu'une dysrégulation précoce du système sérotoninergique induit un large éventail d'altérations comportementales allant de phénotypes anxieux-dépressifs liés au stress à des déficits sociaux. Chez l'homme, des études ont permis de mettre en évidence que des variants génétiques du système sérotoninergique interagissent avec l'adversité précoce et régulent la sécrétion du cortisol induite par le stress et l'activation de circuits cérébraux impliqués dans les troubles de l'humeur. De plus, des données récentes révèlent que l'adversité précoce induit des modifications épigénétiques dans des gènes du système serotoninergique. Finalement, il a pu être récemment démontré que des inhibiteurs sélectifs de la recapture de la sérotonine peuvent réinstaurer des formes de neuroplasticité juvénile permettant d'effacer des souvenirs liés à la peur. Ces approches donnent un éclairage novateur sur les effets biologiques des antidépresseurs et leur application clinique.

Synapses are anatomical specializations at the interface of two neurons. They have fascinated researchers ever since Sherrington coined the term ‘synapse’ in 1879. Studies of synapses have provided amazing insight into their function and were boosted by the discovery, now more than 30 years ago, that synapses can undergo long-term activity-dependent plasticity. Over the last two decades much effort has been devoted to the study of long-term synaptic plasticity as a candidate mechanism underlying learning and memory. More recently dysfunctional synaptic plasticity has been implicated in several brain diseases, such as depression, addiction, dementia and anxiety disorders. Here we report on an international meeting that took place in Geneva in July 2008 that brought together scientists who study synapses and disease mechanisms. Brain diseases constitute a major burden to society. In Europe, alone, it is estimated that direct and indirect costs of brain diseases represent more than 350 billion euros per year. When broken down into individual diseases the most costly are depression (105 billion euros, a sum equal to the cost of all cardiovascular diseases), addiction (56 billion even without including nicotine abuse), dementia (54 billion) and anxiety disorders (40 billion), followed by autism and schizophrenia. The Synaptic Basis of Disease meeting, which was organized as a satellite meeting to the July 2008 FENS meeting in Geneva (Fig. 1), was convened to bring together leading researchers working on basic synaptic mechanisms with those working on neurological disorders. Indeed, many labs at the meeting have programs working on both aspects. The main focus of the meeting was to generate discussion amongst some of the leading experimentalists working on synaptic and disease mechanisms. Figure 1 The poster for the symposium

Objectives: We evaluated the effect of exploratory neurectomy on phantom limb pain (PLP) in patients who had PLP and neuroma findings in the amputated extremity.Methods: The study included 14 patients (13 males, 1 female; mean age 30 years; range 21 to 54 years) who developed symptomatic neurinoma and PLP following amputation of an extremity due to trauma (9 mine blasts, 5 traffic accidents). Postamputation period ranged from 2.5 to 17 years (mean 5.5 years). All the patients had PLP of varying intensity and neuroma symptoms causing the sensation of a small electric shock, aroused by application of prosthesis, contact with bed, or on palpation. The mean visual analog scale (VAS) score for PLP was 8.4 (range 7 to 10) before neurectomy. The mean follow-up was 71.5 months (range 44 to 98 months).Results: Complete recovery from PLP was achieved after neurectomy. Symptoms of neuroma completely disappeared during the follow-up period. Visual analog scale score was 0 in all the patients.Conclusion: The best way to prevent postamputation neuromas and PLP is to cut the nerve as proximal as possible, allowing its retraction into the soft tissue, and leaving its end away from the stump., Amaç: Fantom ekstremite ağrısı (FEA) ve semptomatik nörinom bulgusu olan amputasyonlu olgularda eksploratif nörektominin FEA üzerindeki etkisi değerlendirildi.Çalışma planı: Çalışmaya semptomatik nörinom ve FEA tanısı konan eski amputasyonlu 14 olgu (13 erkek, 1 kadın; ort. yaş 30; dağılım 21-54) alındı. Hastaların hepsinde etyolojik neden travmaydı (9 mayın yaralanması, 5 trafik kazası). Amputasyon sonrası süre 2.5 yıl ile 17 yıl (ort. 5.5 yıl) arasındaydı. Tüm olgularda değişik yoğunlukta FEA ve protez takma, yatakla temas ya da palpasyonla oluşan elektrik çarpması tarzında nörinom semptomları vardı. Eksploraif nörektomi öncesinde FEA’nın görsel analog skala (GAS) değeri ortalama 8.4 (dağılım 7-10) idi. Hastalar ortalama 71.5 ay (dağılım 44-98 ay) izlendi.Sonuçlar: Olguların hepsinde nörektomi sonrasında FEA tamamen geçti. İzlem süresi içinde olguların hiçbirinde nörinom belirtisi görülmedi. Tüm olgularda FEA için GAS değeri 0 idi.Çıkarımlar: Amputasyon sonrası nörinom oluşumunu ve FEA’nın önlenmesi için en iyi yöntemin, sinirin olabildiğince proksimalden kesilip retrakte olmasını sağlamak ve sinir ucunu güdük ucundan uzaklaştırmak olduğunu düşünüyoruz.

International audience; The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks, and ultimately behavior. In this Perspective, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons.

SummaryInhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2+ neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain.

Although the Morris water maze (MWM) is the most frequently used protocol to examine hippocampus-dependent learning in mice, not much is known about the spatio-temporal dynamics of underlying plasticity processes. Here, we studied molecular and cellular hippocampal plasticity mechanisms during early and late phases of spatial learning in the MWM. Quantitative in situ hybridization for the immediate early genes zif268 and Homer1a (H1a) revealed phase-dependent differences in their expression between areas CA1 and CA3. During the initial learning phase, CA1 expression levels of the molecular plasticity marker H1a, but not of the activity reporter gene zif268, were related to task proficiency; whereas no learning-specific changes could be detected in CA3. Simultaneously, the ratio of surface-expressed NMDAR subunits NR2A and NR2B was downregulated as measured by acute slice biotinylation assay, while the total number of surface NMDARs was unaltered. When intrinsic 'somatic' and synaptic plasticity in the CA1-region of hippocampal slices were examined, we found that early learning promotes intrinsic neuronal plasticity as manifested by a reduction of spike frequency adaptation and postburst afterhyperpolarization. At the synaptic level, however, maintenance of long-term potentiation (LTP) in all learning groups was impaired which is most likely due to 'intrinsic' learning-induced LTP which occluded any further electrically induced LTP. Late learning, in contrast, was characterized by re-normalized H1a, NR2A and NR2B expression and neuronal firing, yet a further strengthening of learning-induced LTP. Together, our data support a precisely timed cascade of complex molecular and subcellular transformations occurring from early to late MWM learning.

The T-type Ca2+channels encoded by theCaV3genes are well established electrogenic drivers for burst discharge. Here, using CaV3.3−/−mice we found that CaV3.3 channels trigger synaptic plasticity in reticular thalamic neurons. Burst discharge via CaV3.3 channels induced long-term potentiation at thalamoreticular inputs when coactivated with GluN2B-containing NMDA receptors, which are the dominant subtype at these synapses. Notably, oscillatory burst discharge of reticular neurons is typical for sleep-related rhythms, suggesting that sleep contributes to strengthening intrathalamic circuits.

In the central nervous system, most synapses show a fast mode of neurotransmitter release known as synchronous release followed by a phase of asynchronous release, which extends over tens of milliseconds to seconds. Synapsin II (SYN2) is a member of the multigene synapsin family (SYN1/2/3) of synaptic vesicle phosphoproteins that modulate synaptic transmission and plasticity, and are mutated in epileptic patients. Here we report that inhibitory synapses of the dentate gyrus of Syn II knockout mice display an upregulation of synchronous neurotransmitter release and a concomitant loss of delayed asynchronous release. Syn II promotes γ-aminobutyric acid asynchronous release in a Ca2+-dependent manner by a functional interaction with presynaptic Ca2+ channels, revealing a new role in synaptic transmission for synapsins., The arrival of action potentials at nerve terminals often leads to synchronous neurotransmitter release. Medrihan and colleagues use electrophysiology on mouse hippocampal neurons to show that the vesicle protein Synapsin II promotes GABAergic asynchronous release by interacting with calcium channels.