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

Human mutations of the Na + -activated K + channel Slack (KCNT1) are associated with epilepsy and intellectual disability. Accordingly, Slack knockout mice (Slack -/- ) exhibit cognitive flexibility deficits in distinct behavioral tasks. So far, however, the underlying causes as well as the role of Slack in hippocampus-dependent memory functions remain enigmatic. We now report that infant (P6-P14) Slack -/- lack both hippocampal LTD and LTP, likely due to impaired NMDA receptor (NMDAR) signaling. Postsynaptic GluN2B levels are reduced in infant Slack -/- , evidenced by lower amplitudes of NMDAR-meditated excitatory postsynaptic potentials. Low GluN2B affected NMDAR-mediated Ca 2+ -influx, rendering cultured hippocampal Slack -/- neurons highly insensitive to the GluN2B-specific inhibitor Ro 25-6981. Furthermore, dephosphorylation of the AMPA receptor (AMPAR) subunit GluA1 at S845, which is involved in AMPAR endocytosis during homeostatic and neuromodulator-regulated plasticity, is reduced after chemical LTD (cLTD) in infant Slack -/- . We additionally detect a lack of mGluR-induced LTD in infant Slack -/- , possibly caused by upregulation of the recycling endosome-associated small GTPase Rab4 which might accelerate AMPAR recycling from early endosomes. Interestingly, LTP and mGluR LTD, but not LTD and S845 dephosphorylation after cLTD are restored in adult Slack -/- . This together with normalized expression levels of GluN2B and Rab4 hints to developmental "restoration" of LTP expression despite Slack ablation, whereas in infant and adult brain, NMDAR-dependent LTD induction depends on this channel. Based on the present findings, NMDAR and vesicular transport might represent novel targets for the therapy of intellectual disability associated with Slack mutations. Consequently, careful modulation of hippocampal Slack activity should also improve learning abilities., (© 2021. The Author(s).)

In this paper, we propose a complex neuro-memristive synapse that exhibits the physiological acts of synaptic potentiation and depression of the human-brain. Specifically, the proposed neuromorphic synapse efficiently imitates the synaptic plasticity, especially long-term potentiation (LTP) and depression (LTD), and short-term facilitation (STF) and depression (STD), phenomena of a biological synapse. Similar to biological synapse, the short- or long-term potentiation (STF and LTP) or depression (STD or LTD) of the memristive synapse are distinguished on the basis of time or repetition of input cycles. The proposed synapse is also designed to exhibit the effect of reuptake and neurotransmitters diffusion processes of a bio-synapse. In addition, it exhibits the distinct bio-realistic attributes, i.e., strong stimulation, exponentially decaying conductance trace of synapse, and voltage dependent synaptic responses, of a neuron. The neuro-memristive synapse is designed in SPICE and its bio-realistic functionalities are demonstrated via various simulations.

Both long-term potentiation (LTP) and depression (LTD) of excitatory synapse strength require the Ca 2+ /calmodulin (CaM)-dependent protein kinase II (CaMKII) and its autonomous activity generated by Thr-286 autophosphorylation. Additionally, LTP and LTD are correlated with dendritic spine enlargement and shrinkage that are accompanied by the synaptic accumulation or removal, respectively, of the AMPA-receptor regulatory scaffold protein A-kinase anchoring protein (AKAP) 79/150. We show here that the spine shrinkage associated with LTD indeed requires synaptic AKAP79/150 removal, which in turn requires CaMKII activity. In contrast to normal CaMKII substrates, the substrate sites within the AKAP79/150 N-terminal polybasic membrane-cytoskeletal targeting domain were phosphorylated more efficiently by autonomous compared with Ca 2+ /CaM-stimulated CaMKII activity. This unusual regulation was mediated by Ca 2+ /CaM binding to the substrate sites resulting in protection from phosphorylation in the presence of Ca 2+ /CaM, a mechanism that favors phosphorylation by prolonged, weak LTD stimuli versus brief, strong LTP stimuli. Phosphorylation by CaMKII inhibited AKAP79/150 association with F-actin; it also facilitated AKAP79/150 removal from spines but was not required for it. By contrast, LTD-induced spine removal of AKAP79/150 required its depalmitoylation on two Cys residues within the N-terminal targeting domain. Notably, such LTD-induced depalmitoylation was also blocked by CaMKII inhibition. These results provide a mechanism how CaMKII can indeed mediate not only LTP but also LTD through regulated substrate selection; however, in the case of AKAP79/150, indirect CaMKII effects on palmitoylation are more important than the effects of direct phosphorylation. Additionally, our results provide the first direct evidence for a function of the well-described AKAP79/150 trafficking in regulating LTD-induced spine shrinkage., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)-whose disruption is postulated to increase vulnerability to drug addiction-was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction.

This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer's disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Highlights: [•] Ca2+ permeability of synaptic AMPARs can be altered by trafficking events. [•] GluA2-lacking AMPARs are added to synapses following stimulation. [•] This occurs under specific conditions at a subset of synapses in the CNS. [•] Endosomal trafficking and lateral diffusion from perisynaptic regions are involved. [•] AMPAR interacting proteins regulate this process. [Copyright &y& Elsevier]

Abstract: Dendritic spines provide a compartment for assembly and functional organization of synaptic machinery that plays a fundamental role in neuronal communication and neuroplasticity. Studies in humans as well as in animal models have demonstrated abnormal spine architecture in several psychiatric disorders, including depression and other stress-related illnesses. The negative impact of stress on the density and organization of spines is thought to contribute to the behavioral deficits caused by stress exposure. Moreover, there is now evidence that medication-induced recovery involves changes in synaptic plasticity and dendrite morphology, including increased expression of pre- and postsynaptic plasticity-related proteins, as well as the density and function of axo-spinous synapses. Here we review the evidence from brain imaging and postmortem studies demonstrating that depression is accompanied by structural and functional alterations of cortical and limbic brain regions, including the prefrontal cortex, hippocampus and amygdala. In addition, we present more direct evidence from basic research studies that exposure to stress alters spine morphology, function and plasticity and that antidepressants, particularly new rapid acting agents, reverse these effects. Elucidation of the signaling pathways and molecular mechanisms that control spine synapse assembly and plasticity will contribute to a better understanding of the pathophysiology of depression and development of novel, more effective therapeutic agents. [Copyright &y& Elsevier]

Abstract: Huntington’s disease (HD) is an autosomal dominant tandem repeat expansion disorder involving cognitive, psychiatric and motor symptoms. The expanded trinucleotide (CAG) repeat leads to an extended polyglutamine tract in the huntingtin protein and a subsequent cascade of molecular and cellular pathogenesis. One of the key features of neuropathology, which has been shown to precede the eventual loss of neurons in the cerebral cortex, striatum and other areas, are changes to synapses, including the dendritic protrusions known as spines. In this review we will focus on synapse and spine pathology in HD, including molecular and experience-dependent aspects of pathogenesis. Dendritic spine pathology has been found in both the human HD brain at post mortem as well as various transgenic and knock-in animal models. These changes may help explain the symptoms in HD, and synaptopathy within the cerebral cortex may be particularly important in mediating the psychiatric and cognitive manifestations of this disease. The earliest stages of synaptic dysfunction in HD, as assayed in various mouse models, appears to involve changes in synaptic proteins and associated physiological abnormalities such as synaptic plasticity deficits. In mouse models, synaptic and cortical plasticity deficits have been directly correlated with the onset of cognitive deficits, implying a causal link. Furthermore, following the discovery that environmental enrichment can delay onset of affective, cognitive and motor deficits in HD transgenic mice, specific synaptic molecules shown to be dysregulated by the polyglutamine-induced toxicity were also found to be beneficially modulated by environmental stimulation. This identifies potential molecular targets for future therapeutic developments to treat this devastating disease. [Copyright &y& Elsevier]

Highlights: [•] Synaptic plasticity is thought to be the underlying cellular mechanism for memory. [•] Metaplasticity describes changes that modify the properties of synaptic plasticity. [•] Behavioral metaplasticity describes plasticity changes on a more global level. [ABSTRACT FROM AUTHOR]

Highlights: [•] Stress can result in highly adaptive responses but is also an important risk factor for disease. [•] Acute stress rapidly enhances excitatory synaptic transmission and promotes learning and memory processes. [•] Chronic stress reduces excitatory synaptic transmission and learning and memory. [•] Early life experience has long-lasting effects on excitatory synaptic transmission and dendritic complexity. [ABSTRACT FROM AUTHOR]

Highlights: [•] The actions of NE on monosynaptic connections in the PFC circuitry were characterized. [•] NE selectively depresses excitatory synaptic transmission in P–FS connections. [•] NE has no detectable effect on P–P and FS–P connections. [•] NE apparently exerts distinctly different modulatory actions on identified synapses. [•] Depending on the postsynaptic targets, the effects of NE in PFC are synapse-specific. [ABSTRACT FROM AUTHOR]

Exposure to the group I metabotropic glutamate receptor (mGluR) agonist dihydroxy phenylglycine (DHPG) induces epileptiform activity in the CA3 region of the hippocampus that persists following washout of DHPG. DHPG also can cause long-term depression of synaptic transmission, and at some synapses this may be mediated by endocannabinoids. We evaluated whether the selective cannabinoid type 1 (CB1) receptor antagonists SR 141716 or AM 251 could modify induction of epileptiform activity produced by DHPG exposure. The induction of epileptiform activity by DHPG exposure was significantly reduced by CB1 receptor antagonists, SR 141716 or AM 251. Minimal effects on epileptiform activity were noted once the activity had been induced. In control slices, exposure to DHPG for 30 min produced long-term depression (LTD) of synaptic transmission, on average about a 70% reduction in slope of the field excitatory postsynaptic potential (EPSP). When slices were exposed to both DHPG and SR 141716 (3 μm), LTD did not occur and the population EPSP remained at control values or greater. These results suggest that CB1 receptors mediate some of DHPG effects that result in persistent epileptiform activity, and antagonism of CB1 receptors has antiepileptogenic properties. Paradoxically DHPG also caused LTD of excitatory synaptic transmission in the CA3 region and CB1 receptor antagonism prevents the depression. We hypothesize that the ictal activity induced by DHPG requires depression of synaptic strength and CB1 receptor antagonism prevents this depression and the induction of ictal activity. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Low-frequency stimulation, which does not induce long-term potentiation (LTP) or long-term potentiation (LTD) by itself, suppresses consecutive LTP or LTD induction in vitro. We tested whether a similar interaction occurs in the human motor cortex. Methods: LTP- or LTD-like plasticity was induced using paired associative stimulation (PAS) with 25 and 10ms interstimulus interval and conditioned by suprathreshold repetitive transcranial magnetic stimulation (rTMS) at a frequency of 0.1Hz. Results: RTMS completely abolished the significant increase of motor-evoked potential (MEP) amplitudes after PAS25ms (PAS25ms only: 1.05±0.14 to 1.76±0.66mV, p =0.001; rTMS+PAS25ms: 1.08±0.18 to 1.02±0.44mV, n.s.) and also abolished the significant decrease of MEP amplitudes after PAS10ms (PAS10ms only: 1.00±0.14 to 0.73±0.32mV; rTMS+PAS10ms: 1.15±0.35 to 1.25±0.43mV, p =0.006). RTMS alone did not significantly alter MEP amplitudes but increased SICI and LICI. Conclusions: Low frequency stimulation increases intracortical inhibition and occludes LTP- and LTD-like plasticity in the human motor cortex. Significance: This finding supports the concept that metaplasticity in the human motor cortex follows similar rules as metaplasticity in in vitro experiments. [Copyright &y& Elsevier]

Recent studies have suggested that the development of addictive behaviours shares common features with traditional learning models. Synaptic plasticity, a possible substrate for learning, has been demonstrated in neural reward circuits and might contribute to the learning of addictive behaviours. Changes in the strength of synaptic connections have been investigated in dopaminergic cells of the ventral tegmental area in response to several addictive drugs. Rapid and persistent forms of synaptic plasticity (specifically, long-lasting synaptic potentiation) have been demonstrated to accompany some of the behavioural effects of addictive drugs. We hypothesize that drug-induced synaptic plasticity might play a role in reward-related learning and addiction by modifying the fine tuning of dopaminergic cell firing. [Copyright &y& Elsevier]

Abstract: High-frequency stimulation of lateral perforant path is accompanied by a heterosynaptic long-term depression (LTD) of medial perforant path synaptic responses in both the dentate gyrus and the CA3 region of the hippocampus. We reported previously that LTP induction at lateral perforant path-CA3 synapses is unaffected by NMDA antagonists. However, it is not known if heterosynaptic LTD that is observed in the CA3 region following lateral perforant path stimulation also is independent from NMDA receptors. We address this question in anesthetized adult rats using systemic administration of the competitive NMDA receptor antagonist CPP. Induction of lateral perforant path-CA3 LTP produced a sustained heterosynaptic depression of medial perforant path-CA3 responses. Systemic administration of CPP (10mg/kg) was ineffective in blocking the induction of LTP at lateral perforant path-CA3 responses. However, heterosynaptic LTD of medial perforant path-CA3 responses was blocked completely by CPP. These data indicate that NMDA receptors are not required for the induction of lateral perforant path-CA3 LTP, but are involved in the induction of heterosynaptic LTD that accompanies lateral perforant path activity. The requirement for NMDA receptors for heterosynaptic LTD suggests one functional role of NMDA receptors at termination fields of the lateral perforant path. [Copyright &y& Elsevier]

Long-term potentiation (LTP) and long-term depression (LTD) of the excitatory synaptic inputs plasticity in the hippocampus is believed to underlie certain types of learning and memory. Especially, stressful experiences, well known to produce long-lasting strong memories of the event themselves, enable LTD by low frequency stimulation (LFS, 3 Hz) but block LTP induction by high frequency stimulation (HFS, 200 Hz). However, it is unknown whether stress-affected synaptic plasticity has an impact on the output plasticity. Thus, we have simultaneously studied the effects of stress on synaptic plasticity and neuronal output in the hippocampal CA1 region of anesthetized Wistar rats. Our results revealed that stress increased basal power spectrum of the evoked synchronized-spikes and enabled LTD induction by LFS. The induction of stress-facilitated LTD but not LFS induced persistent decreases of the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges; However, HFS induced LTP in non-stressed animals and increased the power spectrum of the synchronized-spikes, without affecting the frequency of the spontaneous unitary discharges, but HFS failed to induce LTP in stressed animals without affecting the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges. These observations that stress-facilitated LTD induces the output plasticity through the synchronized-spikes and spontaneous unitary discharges suggest that these types of stress-related plasticity may play significant roles in distribution, amplification and integration of encoded information to other brain structures under stressful conditions. [Copyright &y& Elsevier]

Prior studies showed that positive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve the formation of several types of memory in animals and humans. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength. The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. The third drug was cyclothiazide which potently blocks AMPA receptor desensitization. Effects on plasticity were assessed by measuring (i) the likelihood of obtaining stable potentiation when using theta-burst stimulation with three instead of four pulses per burst, (ii) the maximum amount of potentiation under optimal stimulation conditions, and (iii) the effect on long-term depression (LTD). Both benzamides facilitated the formation of stable potentiation induced with three-pulse burst stimulation which is normally ineffective. CX546 in addition increased maximally inducible potentiation after four-pulse burst stimulation from about 50% to 100%. Burst response analysis revealed that CX546 greatly prolonged the duration of depolarization by slowing the decay of the response which thus presumably leads to a more continuous N-methyl-d-aspartate (NMDA) receptor activation. Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings. CX546, but not CX516, also enhanced nearly two-fold the NMDA receptor-dependent long-term depression induced by heterosynaptic 2 Hz stimulation. Tests with recombinant NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on currents mediated by these receptors. These results suggest that (1) modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, (2) modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus.Taken together, our data indicate that AMPA receptor modulators differ substantially in their ability to enhance synaptic potentiation or depression, depending on their particular influence on receptor kinetics, and hence that they may also be differentially effective in influencing higher-order processes such as memory encoding. [Copyright &y& Elsevier]

Sensory experience drives plasticity of the body map in developing and adult somatosensory cortex, but the synaptic mechanisms underlying such plasticity are not well understood. Recently, several mechanisms that are likely to contribute to map plasticity have been directly observed in response to altered experience in vivo. These mechanisms include long-term potentiation and long-term depression at specific excitatory synapses, competition between lemniscal (barrel) and non-lemniscal (septal) processing streams, and regulation of the number of inhibitory synapses. [Copyright &y& Elsevier]

We have investigated metaplasticity of the group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and depotentiation (DP) induced by physiological synaptic stimulation in the medial perforant path of the dentate gyrus in vitro. Group I mGluR-LTD/DP was inhibited by prior preconditioning brief high frequency stimulation (HFS) if the preconditioning HFS induced long-term potentiation (LTP) or if the induction of LTP was inhibited by an NMDA receptor antagonist. The inhibitory effect of the preconditioning HFS on LTD/DP was dependent upon activation of mGluRs, as it was blocked by the presence of the mGluR antagonist (S)-α-methyl-4-carboxyphenylglycine during the preconditioning stimulation. The inhibitory effect of the preconditioning HFS involved stimulation of PKC, as the presence of the PKC inhibitor bisindolylmaleimide (BIS) during the preconditioning stimulation prevented the inhibitory effect of such preconditioning stimulation. Activation of PKC was also necessary for the induction of mGluR-LTD itself, as the PKC inhibitor BIS prevented the induction of the mGluR-LTD. We suggest that the physiological stimulation of mGluRs by the preconditioning stimulation produces a PKC-dependent inactivation of subsequent group I mGluR functioning and thereby an inhibition of induction of group I mGluR-dependent LTD/DP induction. [Copyright &y& Elsevier]

Protein kinases critically regulate synaptic plasticity in the mammalian hippocampus. Cyclic-AMP dependent protein kinase (PKA) is a serine–threonine kinase that has been strongly implicated in the expression of specific forms of long-term potentiation (LTP), long-term depression (LTD), and hippocampal long-term memory. We review the roles of PKA in activity-dependent forms of hippocampal synaptic plasticity by highlighting particular themes that have emerged in ongoing research. These include the participation of distinct isoforms of PKA in specific types of synaptic plasticity, modification of the PKA-dependence of LTP by multiple factors such as distinct patterns of imposed activity, environmental enrichment, and genetic manipulation of signalling molecules, and presynaptic versus postsynaptic mechanisms for PKA-dependent LTP. We also discuss many of the substrates that have been implicated as targets for PKA’s actions in hippocampal synaptic plasticity, including CREB, protein phosphatases, and glutamatergic receptors. Future prospects for shedding light on the roles of PKA are also described from the perspective of specific aspects of synaptic physiology and brain function that are ripe for investigation using incisive genetic, cell biological, and electrophysiological approaches. [Copyright &y& Elsevier]

We investigated the relationship between Arc (activity-regulated cytoskeleton-associated protein) and Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). Arc and CaM kinase II were concentrated in the postsynaptic density. These proteins were accumulated after electroconvulsive treatment. Arc increased about 2.5-fold within 30 min and was maintained at this level for 8 h after the stimulation. CaM kinase II also increased within 30 min and remained at this level for at least 24 h. The interaction of Arc with CaM kinase II was demonstrated using GST-Arc fusion protein, and confirmed in neuroblastoma cells by immunoprecipitation. We examined the function of Arc by introducing Arc cDNA into neuroblastoma cells expressing CaM kinase II. The cells expressing both Arc and CaM kinase II had longer neurites than those expressing CaM kinase II alone. Arc itself did not promote neurite outgrowth. The growth of neurites by Arc was completely blocked by treatment with KN62, an inhibitor of CaM kinases. These results indicated that Arc potentiated the action of CaM kinase II for neurite extension. [Copyright &y& Elsevier]

Correlated pre- and postsynaptic activity is thought to promote maturation of excitatory synapses in the developing brain by directing AMPA receptors to pure NMDA synapses. However, this hypothesis has not been tested in vivo. Here, we have performed such test by inhibiting correlated neural activity in vivo using a single injection of tetanus toxin into the rat hippocampal CA1 area at postnatal day 1. When examined in the acute slice preparation (1–7 days post-injection), there was a strong reduction, down to 20% of control level, in the frequency of glutamatergic and GABAergic spontaneous postsynaptic currents (sPSCs). This activity deprivation led to a growth retardation of CA1 pyramidal neurons and to markedly faster decay kinetics of NMDA sPCSs. However, it did not alter the relationship between AMPA and NMDA sPSCs with respect to either their frequency or amplitude. Thus, although critical for certain aspects of neuronal development, correlated neural activity in the neonatal hippocampus does not seem to promote incorporation of AMPA receptors at pure NMDA synapses. [Copyright &y& Elsevier]

Physiological roles for postsynaptic molecules in synaptogenesis and plasticity are under intense investigation. Recent imaging experiments, including GFP-based and single-particle tracking strategies, reveal rapid movement of synaptic components to and from the postsynaptic sites. Furthermore, specific patterns of neuronal activity and/or activation of specific transmitter receptors trigger selective translocation of postsynaptic components. These emerging dynamic properties of synaptic specializations add another layer of complexity to the signaling mechanisms of CNS synapses. [Copyright &y& Elsevier]

Neuronal responses to electrical activity-induced calcium signals are specified by the localization of the calcium entry site and the spatial properties of the calcium transient. Calcium flux through NMDA receptors located in the synapse initiates changes in synaptic efficacy and promotes pro-survival events, whereas calcium flux through extrasynaptic NMDA receptors is coupled to cell death pathways. The dialogue between the synaptic NMDA receptors and the nucleus is also modulated by extrasynaptic NMDA receptors, which shut down activity of CRE-binding protein (CREB) and antagonize the increase in brain-derived neurotrophic factor (BDNF) expression induced by synaptic NMDA receptors. The specification of the biological response by the localization of the receptor activated is a new concept in neuronal calcium signalling that can explain many of the opposing roles of NMDA receptors. [Copyright &y& Elsevier]

The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-d-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system. [Copyright &y& Elsevier]

Long-term changes in the synaptic efficacy of corticostriatal synapses are believed to be important for regulating the excitatory input to the basal ganglia, and hence for motor learning and certain forms of cognition. Previous reports have suggested that long-term depression (LTD) is the predominant form of plasticity at corticostriatal synapses. However, we report here that tetanic stimulation of the white matter can readily induce long-term potentiation (LTP) at corticostriatal synapses in a sagittal slice preparation. Furthermore, we find that corticostriatal LTP is obtained in the absence of pharmacological manipulation, and is dependent on NMDA receptor activation. In contrast, LTD is rarely observed following tetanic stimulation of the white matter, but in fact requires direct stimulation within the striatum. This striatally induced depression is blocked by both D1 and D2 dopamine receptor antagonists and by NMDA receptor blockade. Pairing of striatal stimulation with tetanic stimulation of the white matter does not prevent the induction, but significantly enhances the magnitude of LTP at corticostriatal synapses. We suggest that the corticostriatal depression reported here most likely involves the recruitment of local striatal circuits and dopaminergic inputs, and thus might explain the predominance of LTD previously reported. Our observation that it is indeed possible to induce LTP at corticostriatal synapses under physiological conditions in vitro has implications for the normal function and control of the basal ganglia in motor learning and cognition. [ABSTRACT FROM AUTHOR]