Different Numbers of Conjunctive Stimuli Induce LTP or LTD in Mouse Cerebellar Purkinje Cell.

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses plays an important role in cerebellum-related motor coordination and learning. LTD is induced by the conjunction of PF stimulation and climbing fiber (CF) stimulation or somatic PC depolarization, while long-term potentiation (LTP) is induced by PF stimulation alone. Therefore, it is considered that different types of stimulation induce different types of synaptic plasticity. However, we found that a small number of conjunctive stimulations (PF + somatic depolarization of PC) induced LTP, but did not induce LTD of a small size. This LTP was not associated with changes in paired-pulse ratio, suggesting postsynaptic origin. Additionally this LTP was dependent on nitric oxide. This LTP was also induced by a smaller number of physiological conjunctive PF and CF stimuli. These results suggested that a larger number or longer period of conjunctive stimulation is required to induce LTD by overcoming LTP. Ca2+ transients at the PC dendritic region was measured by calcium imaging during LTD-inducing conjunctive stimulation. Peak amplitude of Ca2+ transients increased gradually during repetitive conjunctive stimulation. Instantaneous peak amplitude was not different between the early phase and late phase, but the average amplitude was larger in the later phase than in the early phase. These results show that LTD overcomes LTP, and increased Ca2+ integration or a number of stimulations is required for LTD induction.

PI3K couples long-term synaptic potentiation with cofilin recruitment and actin polymerization in dendritic spines via its regulatory subunit p85α.

Long-term synaptic plasticity is typically associated with morphological changes in synaptic connections. However, the molecular mechanisms coupling functional and structural aspects of synaptic plasticity are still poorly defined. The catalytic activity of type I phosphoinositide-3-kinase (PI3K) is required for specific forms of synaptic plasticity, such as NMDA receptor-dependent long-term potentiation (LTP) and mGluR-dependent long-term depression (LTD). On the other hand, PI3K signaling has been linked to neuronal growth and synapse formation. Consequently, PI3Ks are promising candidates to coordinate changes in synaptic strength with structural remodeling of synapses. To investigate this issue, we targeted individual regulatory subunits of type I PI3Ks in hippocampal neurons and employed a combination of electrophysiological, biochemical and imaging techniques to assess their role in synaptic plasticity. We found that a particular regulatory isoform, p85α, is selectively required for LTP. This specificity is based on its BH domain, which engages the small GTPases Rac1 and Cdc42, critical regulators of the actin cytoskeleton. Moreover, cofilin, a key regulator of actin dynamics that accumulates in dendritic spines after LTP induction, failed to do so in the absence of p85α or when its BH domain was overexpressed as a dominant negative construct. Finally, in agreement with this convergence on actin regulatory mechanisms, the presence of p85α in the PI3K complex determined the extent of actin polymerization in dendritic spines during LTP. Therefore, this study reveals a molecular mechanism linking structural and functional synaptic plasticity through the coordinate action of PI3K catalytic activity and a specific isoform of the regulatory subunits.

A computational model elucidating mechanisms and variability in theta burst stimulation responses.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) with unknown underlying mechanisms and highly variable responses across subjects. To investigate these issues, we developed a simple computational model. Our model consisted of two neurons linked by an excitatory synapse that incorporates two mechanisms: short-term plasticity (STP) and spike-timing-dependent plasticity (STDP). We applied a variable-amplitude current through I-clamp with a TBS time pattern to the pre- and post-synaptic neurons, simulating synaptic plasticity. We analyzed the results and provided an explanation for the effects of TBS, as well as the variability of responses to it. Our findings suggest that the interplay of STP and STDP mechanisms determines the direction of plasticity, which selectively affects synapses in extended neurons and underlies functional effects. Our model describes how the timing, number, and intensity of pulses delivered to neurons during rTMS contribute to induced plasticity. This not only successfully explains the different effects of intermittent TBS (iTBS) and continuous TBS (cTBS), but also predicts the results of other protocols such as 10 Hz rTMS. We propose that the variability in responses to TBS can be attributed to the variable span of neuronal thresholds across individuals and sessions. Our model suggests a biologically plausible mechanism for the diverse responses to TBS protocols and aligns with experimental data on iTBS and cTBS outcomes. This model could potentially aid in improving TBS and rTMS protocols and customizing treatments for patients, brain areas, and brain disorders.

Restoring cerebellar-dependent learning.

Behavioral and pharmaceutical interventions reverse defects associated with increased cerebellar long-term depression in a mouse model of Fragile X syndrome.

Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome.

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb-/-), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb-/-mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7-Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.

Exploring the Effect of Arsenic-Containing Hydrocarbon on the Bidirectional Synaptic Plasticity of the Dorsal Hippocampus.

Arsenic-containing hydrocarbons (AsHCs) are common in marine organisms. However, there is little research on their effects on the central nervous system's advanced activities, such as cognition. Bidirectional synaptic plasticity dynamically regulates cognition through the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the effects of AsHCs on bidirectional synaptic plasticity and the underlying molecular mechanisms remain unexplored. This study provides the first evidence that 15 µg As L-1 AsHC 360 enhances bidirectional synaptic plasticity, occurring during the maintenance phase rather than the baseline phase. Further calcium gradient experiments hypothesize that AsHC 360 may enhance bidirectional synaptic plasticity by affecting calcium ion levels. The enhancement of bidirectional synaptic plasticity by 15 µg As L-1 AsHC 360 holds significant implications in improving cognitive function, treating neuro-psychiatric disorders, promoting neural recovery, and enhancing brain adaptability.

Safety assessment of the process Guolong, based on the EREMA Basic technology, used to recycle post-consumer PET into food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process Guolong (EU register number RECYC323), which uses the EREMA Basic technology. The input material is hot caustic washed and dried poly(ethylene terephthalate) (PET) flakes originating from collected post-consumer PET containers, including no more than 5% PET from non-food consumer applications. The flakes are heated in a ■■■■■ reactor under vacuum before being extruded. Having examined the challenge test provided, the Panel concluded that the ■■■■■ decontamination (step 2), for which a challenge test was provided, is critical in determining the decontamination efficiency of the process. The operating parameters to control the performance of this step are temperature, pressure and residence time. It was demonstrated that this recycling process is able to ensure a level of migration of potential unknown contaminants into food below the conservatively modelled migrations of 0.1 and 0.15 µg/kg food, derived from the exposure scenarios for infants and toddlers, when such recycled PET is used at up to 100%. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long-term storage at room temperature or below, with or without hotfill. Articles made of this recycled PET are not intended to be used in microwave or conventional ovens and such uses are not covered by this evaluation.

Synaptic plasticity in human thalamocortical assembloids.

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids. Single-nucleus RNA sequencing revealed that >80% of cells in thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits.

Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression.

Electroconvulsive shocks (ECS) and ketamine are antidepressant treatments with a relatively fast onset of therapeutic effects compared to conventional medication and psychotherapy. While the exact neurobiological mechanisms underlying the antidepressant response of ECS and ketamine are unknown, both interventions are associated with neuroplasticity. Restoration of neuroplasticity may be a shared mechanism underlying the antidepressant efficacy of these interventions. In this systematic review, literature of animal models of depression is summarized to examine the possible role of neuroplasticity in ECS and ketamine on a molecular, neuronal, synaptic and functional level, and specifically to what extent these mechanisms are shared between both interventions. The results highlight that hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) levels are consistently increased after ECS and ketamine. Moreover, both interventions positively affect glutamatergic neurotransmission, astrocyte and neuronal morphology, synaptic density, vasculature and functional plasticity. However, a small number of studies investigated these processes after ECS. Understanding the shared fundamental mechanisms of fast-acting antidepressants can contribute to the development of novel therapeutic approaches for patients with severe depression.

Neurotrophin-3 Rescues Striatal Synaptic Plasticity in Model of Neurodegeneration by PLC Signaling Activation.

BACKGROUND: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington's disease induced by 3-nitropropionic acid (3-NP). In the 3- NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin-3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo. METHODS: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways. RESULTS: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery. CONCLUSION: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.

Mechanisms of Action of TMS in the Treatment of Depression.

Transcranial magnetic stimulation (TMS) is entering increasingly widespread use in treating depression. The most common stimulation target, in the dorsolateral prefrontal cortex (DLPFC), emerged from early neuroimaging studies in depression. Recently, more rigorous casual methods have revealed whole-brain target networks and anti-networks based on the effects of focal brain lesions and focal brain stimulation on depression symptoms. Symptom improvement during therapeutic DLPFC-TMS appears to involve directional changes in signaling between the DLPFC, subgenual and dorsal anterior cingulate cortex, and salience-network regions. However, different networks may be involved in the therapeutic mechanisms for other TMS targets in depression, such as dorsomedial prefrontal cortex or orbitofrontal cortex. The durability of therapeutic effects for TMS involves synaptic neuroplasticity, and specifically may depend upon dopamine acting at the D1 receptor family, as well as NMDA-receptor-dependent synaptic plasticity mechanisms. Although TMS protocols are classically considered 'excitatory' or 'inhibitory', the actual effects in individuals appear quite variable, and might be better understood at the level of populations of synapses rather than individual synapses. Synaptic meta-plasticity may provide a built-in protective mechanism to avoid runaway facilitation or inhibition during treatment, and may account for the relatively small number of patients who worsen rather than improve with TMS. From an ethological perspective, the antidepressant effects of TMS may involve promoting a whole-brain attractor state associated with foraging/hunting behaviors, centered on the rostrolateral periaqueductal gray and salience network, and suppressing an attractor state associated with passive threat defense, centered on the ventrolateral periaqueductal gray and default-mode network.

Exploration of new space elicits phosphorylation of GluA1(Ser831) and S6K and expression of Arc in the hippocampus in vivo as in long-term potentiation.

The brain responds to experience through modulation of synaptic transmission, that is synaptic plasticity. An increase in the strength of synaptic transmission is manifested as long-term potentiation (LTP), while a decrease in the strength of synaptic transmission is expressed as long-term depression (LTD). Most of the studies of synaptic plasticity have been carried out by induction via electrophysiological stimulation. It is largely unknown in which behavioural tasks such synaptic plasticity occurs. Moreover, some stimuli can induce both LTP and LTD, thus making it difficult to separately study the different forms of synaptic plasticity. Two studies have shown that an aversive memory task - inhibitory avoidance learning and contextual fear conditioning - physiologically and selectively induce LTP and an LTP-like molecular change, respectively, in the hippocampus in vivo. Here, we show that a non-aversive behavioural task - exploration of new space - physiologically and selectively elicits a biochemical change in the hippocampus that is a hallmark of LTP. Specifically, we found that exploration of new space induces an increase in the phosphorylation of GluA1(Ser831), without affecting the phosphorylation of GluA1(Ser845), which are biomarkers of early-LTP and not NMDAR-mediated LTD. We also show that exploration of new space engenders the phosphorylation of the translational regulator S6K and the expression of Arc, which are features of electrophysiologically-induced late-LTP in the hippocampus. Therefore, our results show that exploration of new space is a novel non-aversive behavioural paradigm that elicits molecular changes in vivo that are analogous to those occurring during early- and late-LTP, but not during NMDAR-mediated LTD.

Interplay of hippocampal long-term potentiation and long-term depression in enabling memory representations.

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

Alcohol consumption does not impact delta and kappa opioid receptor-mediated synaptic depression in dorsolateral striatum of adult male mice.

Many drugs of abuse, including alcohol, disrupt long-term synaptic depression (LTD) at dorsal striatal glutamate synapses. This disruption is common to many forms of LTD that are mediated by G protein coupled receptors (GPCRs) that signal through the inhibitory Gi/o class of G proteins. A loss of LTD is thought to mediate behavioral changes associated with the development of substance use disorders. We have previously shown in multiple studies that LTD mediated by the Gi/o-coupled mu opioid receptor is disrupted by in vivo opioid and alcohol exposure in adolescent and adult mice. One of our previous studies suggested that LTD mediated by delta and kappa opioid receptors was resistant to the LTD-disrupting properties of in vivo opioid exposure. We hypothesized that delta and kappa opioid receptor-mediated LTD would be exceptions to the generalizable observation that forms of dorsal striatal Gi/o-coupled receptor LTD are disrupted by drugs of abuse. Specifically, we predicted that these forms of LTD would be resistant to the deleterious effects of alcohol consumption, just as they were resistant to opioid exposure. Indeed, in adult male mice that drank alcohol for 3 weeks, delta and kappa opioid receptor-mediated LTD at glutamatergic inputs to direct pathway and indirect pathway medium spiny neurons in the dorsolateral striatum was unaffected by alcohol. These data demonstrate that alcohol effects on GPCR-mediated LTD are not generalizable across all types of Gi/o-coupled GPCRs.

Bidirectional modulation of synaptic transmission by insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity and is an essential factor in learning and memory processes. However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) at layer 2/3 pyramidal neurons (PNs) of the mouse barrel cortex is favored or prevented by IGF-I (10 nM) or IGF-I (7 nM), respectively, when IGF-I is applied 1 h before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10 nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing long-term depression (LTD) of the inhibitory post-synaptic currents (IPSCs), 7 nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain.

Isoform-specific effects of neuronal inhibition of AMPK catalytic subunit on LTD impairments in a mouse model of Alzheimer's disease.

Synaptic dysfunction is highly correlated with cognitive impairments in Alzheimer's disease (AD), the most common dementia syndrome in the elderly. Long-term potentiation (LTP) and long-term depression (LTD) are two primary forms of synaptic plasticity with opposite direction of synaptic efficiency change. Both LTD and LTD are considered to mediate the cellular process of learning and memory. Substantial studies demonstrate AD-associated deficiency of both LTP and LTD. Meanwhile, the molecular signaling mechanisms underlying impairment of synaptic plasticity, particularly LTD, are poorly understood. By taking advantage of the novel transgenic mouse models recently developed in our lab, here we aimed to investigate the roles of AMP-activated protein kinase (AMPK), a central molecular senor that plays a critical role in maintaining cellular energy homeostasis, in regulation of LTD phenotypes in AD. We found that brain-specific suppression of the AMPKα1 isoform (but not AMPKα2 isoform) was able to alleviate mGluR-LTD deficits in APP/PS1 AD mouse model. Moreover, suppression of either AMPKα isoform failed to alleviate AD-related NMDAR-dependent LTD deficits. Taken together with our recent studies on roles of AMPK signaling in AD pathophysiology, the data indicate isoform-specific roles of AMPK in mediating AD-associated synaptic and cognitive impairments.

Dielectric probing of low-temperature degradation resistance of commercial zirconia bio-ceramics.

OBJECTIVES: To investigate the effect of the stability of oxygen vacancies on the low-temperature degradation (LTD) resistance of two kinds of commercial zirconia-based materials (3Y-TZP ceramics and Ce-TZP/Al2O3 composites) via the dielectric probing methods. METHODS: The commercial 3Y-TZP ceramics and Ce-TZP/Al2O3 composites were prepared via conventional solid-state methods. Density, phase content, microstructure, strain, and biaxial flexural strength (BFS) of two materials were investigated using Archimedes method, XRD, SEM, strain-electric field (S-E) loops and ball-on-ring methods, respectively. The concentration of oxygen vacancies before and after LTD of two materials were evaluated using dielectric probing and XPS methods. RESULTS: The XRD analysis revealed that compared to the 3Y-TZP ceramics, the Ce-TZP/Al2O3 composites showed better LTD resistance, without clear LTD. The greater LTD resistance for Ce-TZP/Al2O3 composites was associated with their stability of oxygen vacancies, by higher activation energy based on the dielectric measurements and XPS results. For the 3Y-TZP ceramics that underwent the tetragonal to the monoclinic phase transition during the LTD treatment, the concentration of their oxygen vacancies decreased after LTD. In addition, the Ce-TZP/Al2O3 composites exhibited higher flexural strength and potential fracture toughness based on the BFS testing and strain vs electric field measurement results, indicating a great potential for use in fixed restorative dental applications. SIGNIFICANCE: This work suggested the stability of oxygen vacancies played a key role in the resistance to LTD. Optimizing the stability of the oxygen vacancies is key to the development of more reliable zirconia- based dental biomaterials with greater resistance to LTD.

Learning-induced bidirectional enhancement of inhibitory synaptic metaplasticity.

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

SHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD.

Posttranslational modifications regulate the properties and abundance of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that mediate fast excitatory synaptic transmission and synaptic plasticity in the central nervous system. During long-term depression (LTD), protein tyrosine phosphatases (PTPs) dephosphorylate tyrosine residues in the C-terminal tail of AMPA receptor GluA2 subunit, which is essential for GluA2 endocytosis and group I metabotropic glutamate receptor (mGluR)-dependent LTD. However, as a selective downstream effector of mGluRs, the mGluR-dependent PTP responsible for GluA2 tyrosine dephosphorylation remains elusive at Schaffer collateral (SC)-CA1 synapses. In the present study, we find that mGluR5 stimulation activates Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) by increasing phospho-Y542 levels in SHP2. Under steady-state conditions, SHP2 plays a protective role in stabilizing phospho-Y869 of GluA2 by directly interacting with GluA2 phosphorylated at Y869, without affecting GluA2 phospho-Y876 levels. Upon mGluR5 stimulation, SHP2 dephosphorylates GluA2 at Y869 and Y876, resulting in GluA2 endocytosis and mGluR-LTD. Our results establish SHP2 as a downstream effector of mGluR5 and indicate a dual action of SHP2 in regulating GluA2 tyrosine phosphorylation and function. Given the implications of mGluR5 and SHP2 in synaptic pathophysiology, we propose SHP2 as a promising therapeutic target for neurodevelopmental and autism spectrum disorders.

Synaptopodin is required for long-term depression at Schaffer collateral-CA1 synapses.

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