-
Molecular Pain 2023Synaptic plasticity such as Long-term potentiation (LTP) is a key mechanism for learning in central synapses including the cortex. There are two least two major forms of... (Review)
Review
Synaptic plasticity such as Long-term potentiation (LTP) is a key mechanism for learning in central synapses including the cortex. There are two least two major forms of LTPs: presynaptic LTP and postsynaptic LTP. For postsynaptic LTP, the potentiation of AMPA receptor-mediated responses through protein phosphorylation is thought to be a key mechanism. Silent synapses have been reported in the hippocampus, but it is thought to be mainly present in the cortex during early development, and may contribute to maturation of the cortical circuit. However, recent several lines of evidence demonstrate that silent synapses may exist in mature synapses of adult cortex, and they can be recruited by LTP-inducing protocols, as well as chemical-induced LTP. In pain-related cortical regions, silent synapses may not only contribute to cortical excitation after peripheral injury, but also the recruitment of new cortical circuits as well. Thus, it is proposed that silent synapses and modification of functional AMPA receptors and NMDA receptors may play important roles in chronic pain, including phantom pain.
Topics: Adult; Humans; Gyrus Cinguli; Chronic Pain; Long-Term Potentiation; Neuronal Plasticity; Receptors, AMPA; Synapses
PubMed: 37227022
DOI: 10.1177/17448069231179011 -
Cell Reports Oct 2023Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe disease symptoms resembling psychosis and cause cognitive dysfunction....
Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe disease symptoms resembling psychosis and cause cognitive dysfunction. After passive transfer of patients' cerebrospinal fluid or human monoclonal anti-GluN1-autoantibodies in mice, we find a disrupted excitatory-inhibitory balance resulting from CA1 neuronal hypoexcitability, reduced AMPA receptor (AMPAR) signaling, and faster synaptic inhibition in acute hippocampal slices. Functional alterations are also reflected in widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. NMDAR-Abs amplify network γ oscillations and disrupt θ-γ coupling. A data-informed network model reveals that lower AMPAR strength and faster GABA receptor current kinetics chiefly account for these abnormal oscillations. As predicted in silico and evidenced ex vivo, positive allosteric modulation of AMPARs alleviates aberrant γ activity, reinforcing the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-Ab-induced aberrant synaptic, cellular, and network dynamics provide conceptual insights into NMDAR-Ab-mediated pathomechanisms and reveal promising therapeutic targets that merit future in vivo validation.
Topics: Humans; Mice; Animals; Hippocampus; Synaptic Transmission; Receptors, N-Methyl-D-Aspartate; Neurons; Autoantibodies; Receptors, AMPA
PubMed: 37768823
DOI: 10.1016/j.celrep.2023.113166 -
ELife Oct 2022At CA1→subiculum synapses, alternatively spliced neurexin-1 (Nrxn1) and neurexin-3 (Nrxn3) enhance NMDA-receptors and suppress AMPA-receptors, respectively, without...
At CA1→subiculum synapses, alternatively spliced neurexin-1 (Nrxn1) and neurexin-3 (Nrxn3) enhance NMDA-receptors and suppress AMPA-receptors, respectively, without affecting synapse formation. Nrxn1 and Nrxn3 act by binding to secreted cerebellin-2 (Cbln2) that in turn activates postsynaptic GluD1 receptors. Whether neurexin-Cbln2-GluD1 signaling has additional functions besides regulating NMDA- and AMPA-receptors, and whether such signaling performs similar roles at other synapses, however, remains unknown. Here, we demonstrate using constitutive Cbln2 deletions in mice that at CA1→subiculum synapses, Cbln2 performs no additional developmental roles besides regulating AMPA- and NMDA-receptors. Moreover, low-level expression of functionally redundant Cbln1 did not compensate for a possible synapse-formation function of Cbln2 at CA1→subiculum synapses. In exploring the generality of these findings, we examined the prefrontal cortex where Cbln2 was recently implicated in spinogenesis, and the cerebellum where Cbln1 is known to regulate parallel-fiber synapses. In the prefrontal cortex, Nrxn1-Cbln2 signaling selectively controlled NMDA-receptors without affecting spine or synapse numbers, whereas Nrxn3-Cbln2 signaling had no apparent role. In the cerebellum, conversely, Nrxn3-Cbln1 signaling regulated AMPA-receptors, whereas now Nrxn1-Cbln1 signaling had no manifest effect. Thus, Nrxn1- and Nrxn3-Cbln1/2 signaling complexes differentially control NMDA- and AMPA-receptors in different synapses in diverse neural circuits without regulating synapse or spine formation.
Topics: Animals; Mice; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; N-Methylaspartate; Protein Precursors; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synapses; Calcium-Binding Proteins; Neural Cell Adhesion Molecules
PubMed: 36205393
DOI: 10.7554/eLife.78649 -
Cell Reports Dec 2022Learning and memory rely on changes in postsynaptic glutamergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor (AMPAR) number, spatial...
Learning and memory rely on changes in postsynaptic glutamergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor (AMPAR) number, spatial organization, and function. The Hippo pathway component WW and C2 domain-containing protein 1 (WWC1) regulates AMPAR surface expression and impacts on memory performance. However, synaptic binding partners of WWC1 and its hierarchical position in AMPAR complexes are largely unclear. Using cell-surface proteomics in hippocampal tissue of Wwc1-deficient mice and by generating a hippocampus-specific interactome, we show that WWC1 is a major regulatory platform in AMPAR signaling networks. Under basal conditions, the Hippo pathway members WWC1 and large tumor-suppressor kinase (LATS) are associated, which might prevent WWC1 effects on synaptic proteins. Reduction of WWC1/LATS binding through a point mutation at WWC1 elevates the abundance of WWC1 in AMPAR complexes and improves hippocampal-dependent learning and memory. Thus, uncoupling of WWC1 from the Hippo pathway to AMPAR-regulatory complexes provides an innovative strategy to enhance synaptic transmission.
Topics: Animals; Mice; Receptors, AMPA; Proteomics
PubMed: 36476872
DOI: 10.1016/j.celrep.2022.111766 -
Nature Jun 2021AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning. A diverse array of AMPAR...
AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength. However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1-GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties.
Topics: Amino Acid Sequence; Animals; Calcium Channels; Cryoelectron Microscopy; Hippocampus; Ion Channel Gating; Lipid Metabolism; Lipids; Mice; Mice, Inbred C57BL; Models, Molecular; Protein Multimerization; Protein Subunits; Pyramidal Cells; Receptors, AMPA; Rotation
PubMed: 34079129
DOI: 10.1038/s41586-021-03613-0 -
Cellular and Molecular Life Sciences :... Nov 2023AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus,...
AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1-4 identified in patients with various neurological disorders. These variants produce changes in agonist EC, response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients' clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.
Topics: Humans; Nervous System Diseases; Synaptic Transmission; Receptors, AMPA; Synapses
PubMed: 37921875
DOI: 10.1007/s00018-023-04991-6 -
Proceedings of the National Academy of... Oct 2023AMPA receptors (AMPARs) play a critical role in synaptic plasticity and learning and memory, and dysfunction or dysregulation of AMPARs could lead to various...
AMPA receptors (AMPARs) play a critical role in synaptic plasticity and learning and memory, and dysfunction or dysregulation of AMPARs could lead to various neurological and psychiatric disorders, such as Alzheimer's disease (AD). However, the dynamics and/or longitudinal changes of AMPARs in vivo during AD pathogenesis remain elusive. Here, employing 5xFAD SEP-GluA1 KI mice, we investigated endogenous AMPA receptor dynamics in a whisker deflection-associated Go/No-go learning paradigm. We found a significant increase in synaptosomal AMPA receptor subunits GluA1 in WT mice after learning, while no such changes were detected in 7-mo-old 5xFAD mice. Daily training led to an increase in endogenous spine surface GluA1 in Control mice, while this increase was absent in 5xFAD-KI mice which correlates with its learning defects in Go/No-go paradigm. Furthermore, we demonstrated that the onset of abnormal AMPAR dynamics corresponds temporally with microglia and astrocyte overactivation. Our results have shown that impairments in endogenous AMPA receptor dynamics play an important role in learning deficits in 5xFAD mice and AD pathogenesis.
Topics: Humans; Animals; Mice; Receptors, AMPA; Alzheimer Disease; Learning; Astrocytes; Microglia
PubMed: 37748061
DOI: 10.1073/pnas.2303878120 -
Neuropharmacology Oct 2021AMPA receptors (AMPARs) are fundamental elements in excitatory synaptic transmission and synaptic plasticity in the CNS. Long term potentiation (LTP), a form of synaptic... (Review)
Review
AMPA receptors (AMPARs) are fundamental elements in excitatory synaptic transmission and synaptic plasticity in the CNS. Long term potentiation (LTP), a form of synaptic plasticity which contributes to learning and memory formation, relies on the accumulation of AMPARs at the postsynapse. This phenomenon requires the coordinated recruitment of different elements in the AMPAR complex. Based on recent research reviewed herein, we propose an updated AMPAR trafficking and LTP model which incorporates both extracellular as well as intracellular mechanisms. This article is part of the special Issue on 'Glutamate Receptors - AMPA receptors'.
Topics: Animals; Humans; Long-Term Potentiation; Receptors, AMPA
PubMed: 34271016
DOI: 10.1016/j.neuropharm.2021.108710 -
The Journal of Neuroscience : the... Mar 2021Cocaine experience generates AMPA receptor (AMPAR)-silent synapses in the nucleus accumbens (NAc), which are thought to be new synaptic contacts enriched in...
Cocaine experience generates AMPA receptor (AMPAR)-silent synapses in the nucleus accumbens (NAc), which are thought to be new synaptic contacts enriched in GluN2B-containing NMDA receptors (NMDARs). After drug withdrawal, some of these synapses mature by recruiting AMPARs, strengthening the newly established synaptic transmission. Silent synapse generation and maturation are two consecutive cellular steps through which NAc circuits are profoundly remodeled to promote cue-induced cocaine seeking after drug withdrawal. However, the basic cellular processes that mediate these two critical steps remains underexplored. Using a combination of electrophysiology, viral-mediated gene transfer, and confocal imaging in male rats as well as knock-in (KI) mice of both sexes, our current study characterized the dynamic roles played by AMPARs and NMDARs in generation and maturation of silent synapses on NAc medium spiny neurons after cocaine self-administration and withdrawal. We report that cocaine-induced generation of silent synapses not only required synaptic insertion of GluN2B-containing NMDARs, but also, counterintuitively, involved insertion of AMPARs, which subsequently internalized, resulting in the AMPAR-silent state on withdrawal day 1. Furthermore, GluN2B NMDARs functioned to maintain these cocaine-generated synapses in the AMPAR-silent state during drug withdrawal, until they were replaced by nonGluN2B NMDARs, a switch that allowed AMPAR recruitment and maturation of silent synapses. These results reveal dynamic interactions between AMPARs and NMDARs during the generation and maturation of silent synapses after cocaine experience and provide a mechanistic basis through which new synaptic contacts and possibly new neural network patterns created by these synapses can be manipulated for therapeutic benefit. Studies over the past decade reveal a critical role of AMPA receptor-silent, NMDA receptor-containing synapses in forming cocaine-related memories that drive cocaine relapse. However, it remains incompletely understood how AMPA and NMDA receptors traffic at these synapses during their generation and maturation. The current study characterizes a two-step AMPA receptor trafficking cascade that contributes to the generation of silent synapses in response to cocaine experience, and a two-step NMDA receptor trafficking cascade that contributes to the maturation of these synapses after cocaine withdrawal. These results depict a highly regulated cellular procedure through which nascent glutamatergic synapses are generated in the adult brain after drug experience and provide significant insight into the roles of glutamate receptors in synapse formation and maturation.
Topics: Animals; Cocaine; Cocaine-Related Disorders; Dopamine Uptake Inhibitors; Female; Male; Mice; Neurons; Nucleus Accumbens; Protein Transport; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synapses
PubMed: 33436529
DOI: 10.1523/JNEUROSCI.1918-20.2021 -
The Journal of Neuroscience : the... May 2023Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the...
Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity , we prion-challenged conditional knockout mice (male and female) having deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrP, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration. Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrP), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrP-mediated neurotoxic signaling.
Topics: Male; Female; Mice; Humans; Animals; Prions; Prion Proteins; Receptors, AMPA; Neurons; Prion Diseases; Neurodegenerative Diseases; Endosomal Sorting Complexes Required for Transport
PubMed: 37019623
DOI: 10.1523/JNEUROSCI.1878-22.2023