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GABAergic synaptic inhibition controls circuit function by regulating neuronal plasticity, excitability, and firing. To achieve these goals, inhibitory synapses themselves undergo several forms of plasticity via diverse mechanisms, strengthening and weakening phasic inhibition in response to numerous activity-induced stimuli. These mechanisms include changing the number and arrangement of functional GABA A Rs within the inhibitory postsynaptic domain (iPSD), which can profoundly regulate inhibitory synapse strength. Here, we explore recent advances in our molecular understanding of inhibitory postsynaptic plasticity, with a focus on modulation of the trafficking, protein-protein interactions, nanoscale-organization, and posttranscriptional regulation of GABA A Rs and iPSD proteins. What has emerged is a complex mechanistic picture of how synaptic inhibition is controlled, with critical ramifications for cognition under typical and pathogenic conditions., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca 2+ -dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca 2+ -dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.

In vertebrates, several forms of memory-relevant synaptic plasticity involve postsynaptic rearrangements of glutamate receptors. In contrast, previous work indicates that Drosophila and other invertebrates store memories using presynaptic plasticity of cholinergic synapses. Here, we provide evidence for postsynaptic plasticity at cholinergic output synapses from the Drosophila mushroom bodies (MBs). We find that the nicotinic acetylcholine receptor (nAChR) subunit α5 is required within specific MB output neurons for appetitive memory induction but is dispensable for aversive memories. In addition, nAChR α2 subunits mediate memory expression and likely function downstream of α5 and the postsynaptic scaffold protein discs large (Dlg). We show that postsynaptic plasticity traces can be induced independently of the presynapse, and that in vivo dynamics of α2 nAChR subunits are changed both in the context of associative and non-associative (familiarity) memory formation, underlying different plasticity rules. Therefore, regardless of neurotransmitter identity, key principles of postsynaptic plasticity support memory storage across phyla.

IntroductionThe N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic transmission and is associated with various neurological and psychiatric disorders. Recently, a novel form of postsynaptic plasticity known as NMDAR-based short-term postsynaptic plasticity (STPP) has been identified. It has been suggested that long-lasting glutamate binding to NMDAR allows for the retention of input information in brain slices up to 500 ms, leading to response facilitation. However, the impact of STPP on the dynamics of neuronal populations remains unexplored.MethodsIn this study, we incorporated STPP into a continuous attractor neural network (CANN) model to investigate its effects on neural information encoding in populations of neurons. Unlike short-term facilitation, a form of presynaptic plasticity, the temporally enhanced synaptic efficacy resulting from STPP destabilizes the network state of the CANN by increasing its mobility.ResultsOur findings demonstrate that the inclusion of STPP in the CANN model enables the network state to predictively respond to a moving stimulus. This nontrivial dynamical effect facilitates the tracking of the anticipated stimulus, as the enhanced synaptic efficacy induced by STPP enhances the system's mobility.DiscussionThe discovered STPP-based mechanism for sensory prediction provides valuable insights into the potential development of brain-inspired computational algorithms for prediction. By elucidating the role of STPP in neural population dynamics, this study expands our understanding of the functional implications of NMDAR-related plasticity in information processing within the brain.ConclusionThe incorporation of STPP into a CANN model highlights its influence on the mobility and predictive capabilities of neural networks. These findings contribute to our knowledge of STPP-based mechanisms and their potential applications in developing computational algorithms for sensory prediction.

Animal brains need to store information to construct a representation of their environment. Knowledge of what happened in the past allows both vertebrates and invertebrates to predict future outcomes by recalling previous experience. Although invertebrate and vertebrate brains share common principles at the molecular, cellular, and circuit-architectural levels, there are also obvious differences as exemplified by the use of acetylcholine versus glutamate as the considered main excitatory neurotransmitters in the respective central nervous systems. Nonetheless, across central nervous systems, synaptic plasticity is thought to be a main substrate for memory storage. Therefore, how brain circuits and synaptic contacts change following learning is of fundamental interest for understanding brain computations tied to behavior in any animal. Recent progress has been made in understanding such plastic changes following olfactory associative learning in the mushroom bodies (MBs) of Drosophila A current framework of memory-guided behavioral selection is based on the MB skew model, in which antagonistic synaptic pathways are selectively changed in strength. Here, we review insights into plasticity at dedicated Drosophila MB output pathways and update what is known about the plasticity of both pre- and postsynaptic compartments of Drosophila MB neurons., (© 2024 Pribbenow and Owald; Published by Cold Spring Harbor Laboratory Press.)

Electrophysiological recordings from Purkinje cells in mice show that the potential for induction of long-term depression may vary with molecular identity

Synaptic plasticity [long-term potentiation/depression (LTP/D)], is a cellular mechanism underlying learning. Two distinct types of early LTP/D (E-LTP/D), acting on very different time scales, have been observed experimentally-spike timing dependent plasticity (STDP), on time scales of tens of ms; and behavioral time scale synaptic plasticity (BTSP), on time scales of seconds. BTSP is a candidate for a mechanism underlying rapid learning of spatial location by place cells. Here, a computational model of the induction of E-LTP/D at a spine head of a synapse of a hippocampal pyramidal neuron is developed. The single-compartment model represents two interacting biochemical pathways for the activation (phosphorylation) of the kinase (CaMKII) with a phosphatase, with ion inflow through channels (NMDAR, CaV1,Na). The biochemical reactions are represented by a deterministic system of differential equations, with a detailed description of the activation of CaMKII that includes the opening of the compact state of CaMKII. This single model captures realistic responses (temporal profiles with the differing timescales) of STDP and BTSP and their asymmetries. The simulations distinguish several mechanisms underlying STDP vs. BTSP, including i) the flow of [Formula: see text] through NMDAR vs. CaV1 channels, and ii) the origin of several time scales in the activation of CaMKII. The model also realizes a priming mechanism for E-LTP that is induced by [Formula: see text] flow through CaV1.3 channels. Once in the spine head, this small additional [Formula: see text] opens the compact state of CaMKII, placing CaMKII ready for subsequent induction of LTP., Competing Interests: Competing interests statement:The authors declare no competing interest.

The plasticity of inhibitory transmission is expected to play a key role in the modulation of neuronal excitability and network function. Over the last two decades, the investigation of the determinants of inhibitory synaptic plasticity has allowed distinguishing presynaptic and postsynaptic mechanisms. While there has been a remarkable progress in the characterization of presynaptically-expressed plasticity of inhibition, the postsynaptic mechanisms of inhibitory long-term synaptic plasticity only begin to be unraveled. At postsynaptic level, the expression of inhibitory synaptic plasticity involves the rearrangement of the postsynaptic molecular components of the GABAergic synapse, including GABAA receptors, scaffold proteins and structural molecules. This implies a dynamic modulation of receptor intracellular trafficking and receptor surface lateral diffusion, along with regulation of the availability and distribution of scaffold proteins. This Review will focus on the mechanisms of the multifaceted molecular reorganization of the inhibitory synapse during postsynaptic plasticity, with special emphasis on the key role of protein dynamics to ensure prompt and reliable activity-dependent adjustments of synaptic strength.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.09.057 Byline: Zhiping Wang (1)(2), Jeffrey G. Edwards (3), Nathan Riley (3), D. William Provance (4), Ryan Karcher (4), Xiang-dong Li (5), Ian G. Davison (1)(2), Mitsuo Ikebe (5), John A. Mercer (4), Julie A. Kauer (3), Michael D. Ehlers (1)(2) Keywords: MOLNEURO Abstract: Learning-related plasticity at excitatory synapses in the mammalian brain requires the trafficking of AMPA receptors and the growth of dendritic spines. However, the mechanisms that couple plasticity stimuli to the trafficking of postsynaptic cargo are poorly understood. Here we demonstrate that myosin Vb (MyoVb), a Ca.sup.2+-sensitive motor, conducts spine trafficking during long-term potentiation (LTP) of synaptic strength. Upon activation of NMDA receptors and corresponding Ca.sup.2+ influx, MyoVb associates with recycling endosomes (REs), triggering rapid spine recruitment of endosomes and local exocytosis in spines. Disruption of MyoVb or its interaction with the RE adaptor Rab11-FIP2 abolishes LTP-induced exocytosis from REs and prevents both AMPA receptor insertion and spine growth. Furthermore, induction of tight binding of MyoVb to actin using an acute chemical genetic strategy eradicates LTP in hippocampal slices. Thus, Ca.sup.2+-activated MyoVb captures and mobilizes REs for AMPA receptor insertion and spine growth, providing a mechanistic link between the induction and expression of postsynaptic plasticity. Author Affiliation: (1) Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA (2) Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA (3) Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA (4) McLaughlin Research Institute, Great Falls, MT 59405, USA (5) Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA Article History: Received 2 January 2008; Revised 16 July 2008; Accepted 9 September 2008 Article Note: (miscellaneous) Published: October 30, 2008

Purpose: Chronic intermittent hypoxia (CIH) is a major cause of cognitive dysfunction in people with obstructive sleep apnea syndrome (OSAS), as it damages synapse structure, and function. This study aimed to investigate the potential mechanisms resulting in cognitive impairment caused by CIH in patients with OSAS. Methods: Healthy adult SD male rats (n = 36) were randomly divided into four groups: control, CIH, WP1066, and dimethyl sulfoxide (DMSO). The CIH, WP1066, and DMSO groups were exposed to intermittent hypoxic environments for 8 h per day for 28 d. The WP1066 group received intraperitoneal injection of WP1066, a selective signal transducer and activator of transcription-3 (STAT3) inhibitor. All the experimental rats were subjected to the Morris water maze. Hippocampal tissue samples (n = 6 per group) were used for western blot analysis, and brain tissue samples (n = 3 per group) were used for immunohistochemistry and hematoxylin and eosin staining. Results: The cognition of rats exposed to prolonged CIH was impaired. P-STAT3 expression was found to be higher in CIH rats than in control rats. Postsynaptic density95 (PSD95) expression was significantly reduced in rats with CIH-induced learning and memory impairment, but it significantly increased after the STAT3 signaling pathway was blocked, which improved learning and memory ability. However, inhibition of the STAT3 signaling pathway failed to improve the decline of synaptophysin (SYP) protein caused by CIH. Conclusions: When rats are exposed to CIH, STAT3 in the brain is activated, PSD95 and SYP levels decrease, and cognition is impaired. Inhibition of the STAT3 signaling pathway increases PSD95 to recover postsynaptic plasticity, thereby improving cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Functional and structural alterations of clustered postsynaptic ligand gated ion channels in neuronal cells are thought to contribute to synaptic plasticity and memory formation in the human brain. Here, we describe a novel molecular mechanism for structural alterations of NR1 subunits of the NMDA receptor. In cultured rat spinal cord neurons, chronic NMDA receptor stimulation induces disappearance of extracellular epitopes of NMDA receptor NR1 subunits, which was prevented by inhibiting matrix metalloproteinases (MMPs). Immunoblotting revealed the digestion of solubilized NR1 subunits by MMP-3 and identified a fragment of about 60 kDa as MMPs-activity-dependent cleavage product of the NR1 subunit in cultured neurons. The expression of MMP-3 in the spinal cord culture was shown by immunoblotting and immunofluorescence microscopy. Recombinant NR1 glycine binding protein was used to identify MMP-3 cleavage sites within the extracellular S1 and S2-domains. N-terminal sequencing and site-directed mutagenesis revealed S542 and L790 as two putative major MMP-3 cleavage sites of the NR1 subunit. In conclusion, our data indicate that MMPs, and in particular MMP-3, are involved in the activity dependent alteration of NMDA receptor structure at postsynaptic membrane specializations in the CNS.

Synaptic plasticity [long-term potentiation/depression (LTP/D)], is a cellular mechanism underlying learning. Two distinct types of early LTP/D (E-LTP/D), acting on very different time scales, have been observed experimentally--spike timing dependent plasticity (STDP), on time scales of tens of ms; and behavioral time scale synaptic plasticity (BTSP), on time scales of seconds. BTSP is a candidate for a mechanism underlying rapid learning of spatial location by place cells. Here, a computational model of the induction of E-LTP/D at a spine head of a synapse of a hippocampal pyramidal neuron is developed. The single-compartment model represents two interacting biochemical pathways for the activation (phosphorylation) of the kinase (CaMKII) with a phosphatase, with ion inflow through channels (NMDAR, CaV1,Na). The biochemical reactions are represented by a deterministic system of differential equations, with a detailed description of the activation of CaMKII that includes the opening of the compact state of CaMKII. This single model captures realistic responses (temporal profiles with the differing timescales) of STDP and BTSP and their asymmetries. The simulations distinguish several mechanisms underlying STDP vs. BTSP, including i) the flow of Ca2+ through NMDAR vs. CaV1 channels, and ii) the origin of several time scales in the activation of CaMKII. The model also realizes a priming mechanism for E-LTP that is induced by Ca2+ flow through CaV1.3 channels. Once in the spine head, this small additional Ca2+ opens the compact state of CaMKII, placing CaMKII ready for subsequent induction of LTP. [ABSTRACT FROM AUTHOR]

Cerebellar learning is expressed as upbound or downbound changes in simple spike activity of Purkinje cell subpopulations, but the underlying mechanism remains enigmatic. By visualizing murine Purkinje cells with different molecular identities, we demonstrate that the potential for induction of long-term depression is prominent in downbound and minimal in the upbound subpopulation. These differential propensities depend on the expression profile, but not on the synaptic inputs, of the individual Purkinje cell involved, highlighting the functional relevance of intrinsic properties for memory formation. Electrophysiological recordings from Purkinje cells in mice show that the potential for induction of long-term depression may vary with molecular identity [ABSTRACT FROM AUTHOR]

The long-range trafficking of newly synthesized postsynaptic proteins and the local rules that govern postsynaptic trafficking at individual synapses are discussed. The analysis focused on the trafficking events that take place following local dendritic translation, although local mRNA translation in dendrites have played an important role in localizing a number of postsynaptic proteins.

G-protein-coupled receptors (GPCRs) may form heteromeric complexes and cooperatively mediate cellular responses. Although heteromeric GPCR complexes are suggested to occur in many neurons, their contribution to neuronal function remains unclear. We address this question using two GPCRs expressed in cerebellar Purkinje cells: adenosine A1 receptor (A1R), which regulates neurotransmitter release and neuronal excitability in central neurons, and type-1 metabotropic glutamate receptor (mGluR1), which mediates cerebellar long-term depression, a form of synaptic plasticity crucial for cerebellar motor learning. We examined interaction between these GPCRs by immunocytochemical, biochemical, and Förster resonance energy transfer analyses in cultured mouse Purkinje cells and heterologous expression cells. These analyses revealed that the GPCRs closely colocalized and formed heteromeric complexes on the cell surfaces. Furthermore, our electrophysiological analysis showed that CSF levels (40-400 nm) of adenosine or synthetic A1R agonists with comparable potencies blocked mGluR1-mediated long-term depression of the postsynaptic glutamate-responsiveness (glu-LTD) of cultured Purkinje cells. A similar dose of the A1R agonist decreased the ligand affinity of mGluR1 and did not affect depolarization-induced Ca(2+) influx, which is an essential factor in inducing glu-LTD. The A1R agonist did not affect glu-LTD mimicked by direct activation of protein kinase C. These results suggest that A1R blocked glu-LTD by decreasing the ligand sensitivity of mGluR1, but not the coupling efficacy from mGluR1 to the intracellular signaling cascades. These findings provide a new insight into neuronal GPCR signaling and demonstrate a novel regulatory mechanism of synaptic plasticity.

The functional reconfiguration of central neuronal networks, a phenomenon by which neurons change their participation in network operation, is important for organizing adaptive behaviors. Such reconfiguration can be expressed in a long-lasting manner (hours, days) after a training paradigm. The present study shows that such a long-lasting network reconfiguration requires a cooperation of both presynaptic and postsynaptic modifications in a neuronal interaction between two functionally distinct networks. In isolated preparations of the lobster stomatogastric nervous system, the single ventral dilator (VD) neuron can switch its functional participation from one discrete network (the pyloric network) to another (the cardiac sac network). This switching capability can be long-lasting and can be induced by a sensitizing procedure. A persistent change that was associated with this neuronal switching was found in each of the two networks. First, the intrinsic membrane properties of the VD neuron that allow it to participate spontaneously in the pyloric network are altered. Second, bursting activity is strengthened in the inferior ventricular neurons that both drive cardiac sac network activity and monosynaptically excite the VD neuron in phase with this network activity. Importantly, these changes in intrinsic properties of both presynaptic and postsynaptic neurons are required to allow the VD neuron switching, because expression of either the presynaptic or the postsynaptic change alone did not permit VD neuron switching to occur. These results suggest that a cooperative modification of a discrete network interaction is able to persistently switch the output pattern of a motor neuron as a result of a sensitizing paradigm.

Simulation studies were performed in a model of neuronal dendrite with Na+ and K+ channels and with ionotropic and metabotropic glutamate receptors. The ionotropic receptors were either N-methyl-D-aspartate (NMDA)-sensitive, voltage-dependent, and permeable to Ca2+, Na+, and K+, or non-NMDA-sensitive, voltage-independent, and permeable to Na+ and K+. The metabotropic receptors provided a catalytic effect on Ca2+-induced Ca2+ release from intracellular stores. Local intracellular concentration [Ca2+]i in the cytoplasm was changed because of exchange with the stores, axial diffusion, and transmembrane inward passive and outward pump fluxes. Tonic activation of ionotropic and metabotropic receptors in a particular range of intensities triggered the formation of spatially periodic [Ca2+]i hot and cold bands arising from an initial uniform state. The period and width of the bands were smaller at higher levels of tonic NMDA activation and higher metabotropically controlled rates of Ca2+-induced Ca2+ release. The bandwidths also depended on the dendrite diameter, the specific membrane, and cytoplasm resistivity. This activity-induced pattern led to long-term, spatially inhomogeneous change in local excitatory postsynaptic potentials (EPSPs) of NMDA synapses phasically activated with the same presynaptic intensity. The phasic EPSPs were potentiated if the synapse occurred in the hot band.

The plasticity of inhibitory transmission is expected to play a key role in the modulation of neuronal excitability and network function. Over the last two decades, the investigation of the determinants of inhibitory synaptic plasticity has allowed distinguishing pre-synaptic and postsynaptic mechanisms. While there has been a remarkable progress in the characterization of presynaptically-expressed plasticity of inhibition, the postsynaptic mechanisms of inhibitory long-term synaptic plasticity only begin to be unraveled. At postsynaptic level, the expression of inhibitory synaptic plasticity involves the rearrangement of the postsynaptic molecular components of the GABAergic synapse, including GABAA receptors, scaffold proteins and structural molecules. This implies a dynamic modulation of receptor intracellular trafficking and receptor surface lateral diffusion, along with regulation of the availability and distribution of scaffold proteins. This Review will focus on the mechanisms of the multifaceted molecular reorganization of the inhibitory synapse during postsynaptic plasticity, with special emphasis on the key role of protein dynamics to ensure prompt and reliable activity-dependent adjustments of synaptic strength. [ABSTRACT FROM AUTHOR]

Motor nerve terminal outgrowth (NTO) at neuromuscular junctions (NMJs) occurs rapidly in response to denervation changes in muscle. We have previously found that NTO can produce an elongation of the synaptic area of the NMJ as defined by cholinesterase-silver staining. In the present study, we examined the effects of NTO on a postsynaptic muscle membrane component, the usually stable cluster of acetylcholine receptors (AChRs) at the NMJ. NTO was evoked in rat soleus muscles using botulinum toxin. AChRs were demonstrated using immunocytochemistry or autoradiography of alpha-bungarotoxin binding. Our results show that NTO induces rapid elongation of the cluster of AChRs at the NMJ within 7 d of treatment with botulinum toxin. The growth in the size of the AChR clusters was accompanied by an increase in the number of AChRs/NMJ. No elongation of AChR clusters was seen following surgical denervation, suggesting that cluster growth is related to NTO and not to denervation changes in muscle per se. Growth of NMJ-AChR clusters appeared to result primarily from 2 processes: insertion of new AChRs into the NMJ membrane and, surprisingly, redistribution of preexisting NMJ-AChRs. These results show that NTO can cause rapid changes in the normally stable cluster of AChRs at the NMJ. Motor nerve terminals provide a strong and anatomically precise control of AChRs at the NMJ.

We model a small system of hypothetical neurons having ongoing afferent input ("stimulus") short-term refraction/inhibition, and brief-latency intercellular excitatory feedback loops. We incorporate postsynaptic plasticity: synapses onto a given cell are grouped into dendritic "neighborhoods" wherein sufficiently large local postsynaptic potentials sums cause proportional changes in local synaptic efficacy. The efficacies record multiple cell-to-cell and time-to-time correlations. The efficacy patterns fall into several classes, for each of which there is a stereotypical relationship leading from "steady-state" stimuli to corresponding sets of possible "responses" (periodic firing patterns). We examine the system's ability to discriminate between stimuli via firing patterns and to retain information during change of efficacies. There is an optimal region for efficacy configurations inside of which discrimination is good and outside of which the system can be inactive, particularly forgetful, or perseverative. We find that stimulus discrimination is enhanced by divergence and convergence in the pattern of afferent input. Perseverative firing patterns, invoked or suppressed by cotransmitters, can play a role in associative activities of the network.

G-protein-coupled receptors (GPCRs) may form heteromeric complexes and cooperatively mediate cellular responses. Although heteromericGPCRcomplexes are suggested to occur inmanyneurons, their contribution to neuronal function remains unclear. We address this question using two GPCRs expressed in cerebellar Purkinje cells: adenosine A1 receptor (A1R), which regulates neurotransmitter release and neuronal excitability in central neurons, and type-1 metabotropic glutamate receptor (mGluR1), which mediates cerebellar longterm depression, a form of synaptic plasticity crucial for cerebellar motor learning. We examined interaction between these GPCRs by immunocytochemical, biochemical, and Forster resonance energy transfer analyses in cultured mouse Purkinje cells and heterologous expression cells. These analyses revealed that the GPCRs closely colocalized and formed heteromeric complexes on the cell surfaces. Furthermore, our electrophysiological analysis showed that CSF levels (40-400 nM) of adenosine or synthetic A1R agonists with comparable potencies blocked mGluR1-mediated long-term depression of the postsynaptic glutamate-responsiveness (glu-LTD) of cultured Purkinje cells. A similar dose of the A1R agonist decreased the ligand affinity of mGluR1 and did not affect depolarization-induced Ca2 influx, which is an essential factor in inducing glu-LTD. The A1R agonist did not affect glu-LTD mimicked by direct activation of protein kinase C. These results suggest that A1R blocked glu-LTD by decreasing the ligand sensitivity of mGluR1, but not the coupling efficacy from mGluR1 to the intracellular signaling cascades. These findings provide a new insight into neuronalGPCRsignaling and demonstrate a novel regulatory mechanism of synaptic plasticity. [ABSTRACT FROM AUTHOR]

Functional and structural alterations of clustered postsynaptic ligand gated ion channels in neuronal cells are thought to contribute to synaptic plasticity and memory formation in the human brain. Here, we describe a novel molecular mechanism for structural alterations of NR1 subunits of the NMDA receptor. In cultured rat spinal cord neurons, chronic NMDA receptor stimulation induces disappearance of extracellular epitopes of NMDA receptor NR1 subunits, which was prevented by inhibiting matrix metalloproteinases (MMPs). Immunoblotting revealed the digestion of solubilized NR1 subunits by MMP-3 and identified a fragment of about 60 kDa as MMPs-activity-dependent cleavage product of the NR1 subunit in cultured neurons. The expression of MMP-3 in the spinal cord culture was shown by immunoblotting and immunofluorescence microscopy. Recombinant NR1 glycine binding protein was used to identify MMP-3 cleavage sites within the extracellular S1 and S2-domains. N-terminal sequencing and site-directed mutagenesis revealed S542 and L790 as two putative major MMP-3 cleavage sites of the NR1 subunit. In conclusion, our data indicate that MMPs, and in particular MMP-3, are involved in the activity dependent alteration of NMDA receptor structure at postsynaptic membrane specializations in the CNS. [ABSTRACT FROM AUTHOR]

Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from postmortem RNA expression studies (CommonMind gene-expression datasets) to assess the consequences of altered expression of plasticity-regulating genes for the amplitude of LTP and LTD. Our results show that the expression alterations observed post mortem, especially those in the anterior cingulate cortex, lead to impaired protein kinase A (PKA)-pathwaymediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped electroencephalogram (EEG) dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials were determined for 286 healthy controls. Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder. [ABSTRACT FROM AUTHOR]