Contribution of Postsynaptic AMPA Receptor Channels to the Short- and Long-Term Synaptic Plasticity

The author briefly summarizes his own experimental data obtained earlier and reports evidence in favor of the contribution of postsynaptic AMPA receptor channels to the mechanisms underlying modifications of excitatory synaptic transmission in the CNS (in particular, in neocortical and hippocampal neuronal circuits).     

神经元的突触可塑性与学习和记忆

大量研究表明,神经元的突触可塑性包括功能可塑性和结构可塑性,与学习和记忆密切相关.最近,在经过训练的动物海马区,记录到了学习诱导的长时程增强(long term potentiation,LTP),如果用激酶抑制剂阻断晚期LTP,就会使大鼠丧失训练形成的记忆.这些结果指出,LTP可能是形成记忆的分子基础.因此,进一步研究哺乳动物脑内突触可塑性的分子机制,对揭示学习和记忆的神经基础有重要意义.此外,在精神迟滞性疾病和神经退行性疾病患者脑内记录到异常的LTP,并发现神经元的树突棘数量减少,形态上产生畸变或萎缩,同时发现,产生突变的基因大多编码调节突触可塑性的信号通路蛋白,故突触可塑性研究也将促进精神和神经疾病的预防和治疗.综述了突触可塑性研究的最新进展,并展望了其发展前景.     

Subunit-dependent and subunit-independent rules of AMPA receptor trafficking during chemical long-term depression in hippocampal neurons

Long-term potentiation (LTP) and long-term depression (LTD) of excitatory neurotransmission are believed to be the neuronal basis of learning and memory. Both processes are primarily mediated by neuronal activity–induced transport of postsynaptic AMPA-type glutamate receptors (AMPARs). While AMPAR subunits and their specific phosphorylation sites mediate differential AMPAR trafficking, LTP and LTD could also occur in a subunit-independent manner. Thus, it remains unclear whether and how certain AMPAR subunits with phosphorylation sites are preferentially recruited to or removed from synapses during LTP and LTD. Using immunoblot and immunocytochemical analysis, we show that phosphomimetic mutations of the membrane-proximal region (MPR) in GluA1 AMPAR subunits affect the subunit-dependent endosomal transport of AMPARs during chemical LTD. AP-2 and AP-3, adaptor protein complexes necessary for clathrin-mediated endocytosis and late endosomal/lysosomal trafficking, respectively, are reported to be recruited to AMPARs by binding to the AMPAR auxiliary subunit, stargazin (STG), in an AMPAR subunit–independent manner. However, the association of AP-3, but not AP-2, with STG was indirectly inhibited by the phosphomimetic mutation in the MPR of GluA1. Thus, although AMPARs containing the phosphomimetic mutation at the MPR of GluA1 were endocytosed by a chemical LTD-inducing stimulus, they were quickly recycled back to the cell surface in hippocampal neurons. These results could explain how the phosphorylation status of GluA1-MPR plays a dominant role in subunit-independent STG-mediated AMPAR trafficking during LTD.     

Cholinergic Neurotransmission and Synaptic Plasticity Concerning Memory Processing

The brain is able to change the synaptic strength in response to stimuli that leave a memory trace. Long-term potentiation (LTP) and long-term depression (LTD) are forms of activity-dependent synaptic plasticity proposed to underlie memory. The induction of LTP appears mediated by glutamate acting on AMPA and then on NMDA receptors. Cholinergic muscarinic agonists facilitate learning and memory. Acetylcholine depolarizes pyramidal neurons, reduces inhibition, upregulates NMDA channels and activates the phosphoinositide cascade. Postsynaptic Ca²⁺ rises and stimulates Ca-dependent PK, promoting synaptic changes. Electroencephalographic desynchronization and hippocampal theta rhythm are related to learning and memory, are inducible by Cholinergic agonists and elicited by hippocampal Cholinergic terminals. Their loss results in memory deficits. Hence, Cholinergic pathways may act synergically with glutamatergic transmission, regulating and leading to synaptic plasticity. The stimulation that induces plasticity in vivo has not been established. The patterns for LTP/LTD induction in vitro may be due to the loss of ascending Cholinergic inputs. As a rat explores pyramidal cells fire bursts that could be relevant to plasticity.     

Myosin IIb-dependent Regulation of Actin Dynamics Is Required for N-Methyl-d-aspartate Receptor Trafficking during Synaptic Plasticity

N-Methyl-d-aspartate receptor (NMDAR) synaptic incorporation changes the number of NMDARs at synapses and is thus critical to various NMDAR-dependent brain functions. To date, the molecules involved in NMDAR trafficking and the underlying mechanisms are poorly understood. Here, we report that myosin IIb is an essential molecule in NMDAR synaptic incorporation during PKC- or θ burst stimulation-induced synaptic plasticity. Moreover, we demonstrate that myosin light chain kinase (MLCK)-dependent actin reorganization contributes to NMDAR trafficking. The findings from additional mutual occlusion experiments demonstrate that PKC and MLCK share a common signaling pathway in NMDAR-mediated synaptic regulation. Because myosin IIb is the primary substrate of MLCK and can regulate actin dynamics during synaptic plasticity, we propose that the MLCK- and myosin IIb-dependent regulation of actin dynamics is required for NMDAR trafficking during synaptic plasticity. This study provides important insights into a mechanical framework for understanding NMDAR trafficking associated with synaptic plasticity.     

Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on

This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors.     

The Regulation of Synaptic Protein Turnover

Emerging evidence indicates that protein synthesis and degradation are necessary for the remodeling of synapses. These two processes govern cellular protein turnover, are tightly regulated, and are modulated by neuronal activity in time and space. The anisotropic anatomy of the neurons presents a challenge for the study of protein turnover, but the understanding of protein turnover in neurons and its modulation in response to activity can help us to unravel the fine-tuned changes that occur at synapses in response to activity. Here we review the key experimental evidence demonstrating the role of protein synthesis and degradation in synaptic plasticity, as well as the turnover rates of specific neuronal proteins.     

Emerging role of AMPA receptor subunit GluA1 in synaptic plasticity: Implications for Alzheimer's disease

It is well established that GluA1 mediated synaptic plasticity plays a central role in the early development of AD. The complex cellular and molecular mechanisms that enable GluA1‐related synaptic regulation remain to fully understood. Particularly, understanding the mechanisms that disrupt GluA1 related synaptic plasticity is central to the development of disease‐modifying therapies which are sorely needed as the incidence of AD rises. We surmise that the published evidence establishes deficits in synaptic plasticity as a central factor of AD aetiology. We additionally highlight potential therapeutic strategies for the treatment of AD, and we delve into the roles of GluA1 in learning and memory. Particularly, we review the current understanding of the molecular interactions that confer the actions of this ubiquitous excitatory receptor subunit including post‐translational modification and accessory protein recruitment of the GluA1 subunit. These are proposed to regulate receptor trafficking, recycling, channel conductance and synaptic transmission and plasticity.     

Disruption of MET Receptor Tyrosine Kinase,an Autism Risk Factor,Impairs Developmental Synaptic Plasticity in the Hippocampus

As more genes conferring risks to neurodevelopmental disorders are identified, translating these genetic risk factors into biological mechanisms that impact the trajectory of the developing brain is a critical next step. Here, we report that disrupted signaling mediated MET receptor tyrosine kinase (RTK), an established risk factor for autism spectrum disorders, in the developing hippocampus glutamatergic circuit leads to profound deficits in neural development, synaptic transmission, and plasticity. In cultured hippocampus slices prepared from neonatal mice, pharmacological inhibition of MET kinase activity suppresses dendritic arborization and disrupts normal dendritic spine development. In addition, single‐neuron knockdown (RNAi) or overexpression of Met in the developing hippocampal CA1 neurons leads to alterations, opposite in nature, in basal synaptic transmission and long‐term plasticity. In forebrain‐specific Met conditional knockout mice (Met^fx/fx;emx1^cre), an enhanced long‐term potentiation (LTP) and long‐term depression (LTD) were observed at early developmental stages (P12–14) at the Schaffer collateral to CA1 synapses compared with wild‐type littermates. In contrast, LTP and LTD were markedly reduced at young adult stage (P56–70) during which wild‐type mice show robust LTP and LTD. The altered trajectory of synaptic plasticity revealed by this study indicate that temporally regulated MET signaling as an intrinsic, cell autonomous, and pleiotropic mechanism not only critical for neuronal growth and functional maturation, but also for the timing of synaptic plasticity during forebrain glutamatergic circuits development.     

PKC anchoring to GluR4 AMPA receptor subunit modulates PKC-driven receptor phosphorylation and surface expression

Changes in the synaptic content of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors lead to synaptic efficacy modifications, involved in synaptic plasticity mechanisms believed to underlie learning and memory formation. Early in development, GluR4 is highly expressed in the hippocampus, and GluR4-containing AMPA receptors are inserted into synapses. During synapse maturation, the number of AMPA receptors at the synapse is dynamically regulated, and both addition and removal of receptors from postsynaptic sites occur through regulated mechanisms. GluR4 delivery to synapses in rat hippocampal slices was shown to require protein kinase A (PKA)-mediated phosphorylation of GluR4 at serine 842 (Ser842). Protein kinase C (PKC) can also phosphorylate Ser842, and we have shown that PKCgamma can associate with GluR4. Here we show that activation of PKC in retina neurons, or in human embryonic kidney 293 cells cotransfected with GluR4 and PKCgamma, increases GluR4 surface expression and Ser842 phosphorylation. Moreover, mutation of amino acids R821A, K825A and R826A at the GluR4 C-terminal, within the interacting region of GluR4 with PKCgamma, abolishes the interaction between PKCgamma and GluR4 and prevents the stimulatory effect of PKCgamma on GluR4 Ser842 phosphorylation and surface expression. These data argue for a role of anchored PKCgamma in Ser842 phosphorylation and targeting to the plasma membrane. The triple GluR4 mutant is, however, phosphorylated by PKA, and it is targeted to the synapse in CA1 hippocampal neurons in organotypic rat hippocampal slices. The present findings show that the interaction between PKCgamma and GluR4 is specifically required to assure PKC-driven phosphorylation and surface membrane expression of GluR4.     

Thematic Minireview Series: Molecular Mechanisms of Synaptic Plasticity

The human brain contains ∼86 billion neurons, which are precisely organized in specific brain regions and nuclei. High fidelity synaptic communication between subsets of neurons in specific circuits is required for most human behaviors, and is often disrupted in neuropsychiatric disorders. The presynaptic axon terminals of one neuron release neurotransmitters that activate receptors on multiple postsynaptic neuron targets to induce electrical and chemical responses. Typically, postsynaptic neurons integrate signals from multiple presynaptic neurons at thousands of synaptic inputs to control downstream communication to the next neuron in the circuit. Importantly, the strength (or efficiency) of signal transmission at each synapse can be modulated on time scales ranging up to the lifetime of the organism. This “synaptic plasticity” leads to changes in overall neuronal circuit activity, resulting in behavioral modifications. This series of minireviews will focus on recent advances in our understanding of the molecular and cellular mechanisms that control synaptic plasticity.     

AMPA受体转运及其调控的分子机制

α-氨-3-羟基-5-甲基-4-异恶唑丙酸受体（α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors,AMPA receptors）介导中枢神经系统（CNS）绝大多数快兴奋性突触传递,在学习、记忆和认知等方面具有重要功能. 突触AMPA受体的数量、分布和亚基组成是调节突触传递强度的一个主要机制,与AMPA受体转运密切相关. 最新研究显示,异常的AMPA受体转运与阿尔茨海默病（Alzheimer’s disease,AD）、脆性X综合征(fragile X syndrome, FXS)等神经疾病有关. 本文主要针对AMPA受体转运及其调控的分子机制做一综述,以期为AD、FXS等神经疾病提供新的治疗靶点和途径.     

Pre- and Post-Synaptically Induced Short-Term Plasticity of GABA-ergic Synaptic Transmission

In this communication, the published data and some results of studies of the authors dealing with the problem of short-term plasticity of GABA-ergic synaptic transmission in cerebral structures are described. Neirofiziologiya/Neurophysiology, Vol. 37, No. 3, pp. 294–307, May–June, 2005.     

Down-Regulation of AMPA Receptor Subunit GluR2 in Amygdaloid Kindling

Abstract: Alterations in glutamatergic transmission are postulated to be important in kindling and epilepsy. The levels of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunits (GluR1, 2, and 4) were compared in amygdalakindled and sham-operated animals using subunit-specific antibodies and quantitative western blotting. Four limbic regions were examined: limbic forebrain, piriform cortex/amygdala, hippocampus, and entorhinal cortex. When subunit levels were examined 24 h after the last stage 5 seizure, levels of GluR2 were found to be selectively reduced in limbic forebrain (30%) and piriform cortex/amygdala (25%), with no changes in other regions examined. In addition, no changes in the other subunits were observed in any region. The decrease in GluR2 that was observed in kindled animals at 24 h was no longer present at 1 week and 1 month after the last stage 5 seizure. Because the GluR2 subunit uniquely determines the calcium permeability of these receptors and because the piriform cortex has been implicated as a source of excitatory drive for limbic seizures, reduced GluR2 expression may be important in increasing neuronal excitability in kindling-induced epilepsy, or may reflect a compensatory mechanism resulting from kindling.     

Neurotransmitter Receptor Trafficking and the Regulation of Synaptic Strength

Modulation of the strength of synapses is thought to be one of the mechanisms that underlies learning and memory and is also likely to be important in processes of neuropathology and drug tolerance. This review focuses on the emerging role of postsynaptic neurotransmitter receptor trafficking as an essential mechanism underlying the dynamic regulation of synaptic strength.     

Spike Timing-Dependent Synaptic Plasticity in Visual Cortex: A Modeling Study

Recent studies show that synaptic modification depends critically on the relative spike timing of pre- and postsynaptic neurons. Here we explore the functional implications of spike timing-dependent synaptic plasticity in the visual cortex using a model circuit with modifiable intracortical excitatory connections. First we simulated the experiments using two-point stimuli, in which two visual stimuli in a topographically represented feature space were repeatedly presented in quick succession, and found that tuning of the cortical neurons was modified in a manner similar to that observed experimentally. We then explored the dependence of results on the model parameter and identified the intracortical parameters that were critical for the magnitude of the shifts and obtained a simple relationship between the amount of shift and (S = (_EXTC^rec_exc)/_INHC^rec_inh). Finally we investigated the effects of moving stimuli in a topographically represented visual space and found that they can effectively induce spike timing-dependent modification of the intracortical connections. It suggests the importance of moving stimuli in dynamic modification of the cortical maps through spike timing-dependent synaptic plasticity.     

Autoantibodies Against an Extracellular Peptide of the GluR3 Subtype of AMPA Receptors Activate Both Homomeric and Heteromeric AMPA Receptor Channels

Autoantibodies to the GluR3-subtype of AMPA/glutamate receptors are found in the sera and cerebrospinal fluid of some individuals with epilepsy. They could possibly play a role in the pathophysiology of epilepsy since anti-GluR3 sera display glutamatergic agonist activity. We have investigated here the ability of affinity-purified antibodies (Abs) directed against the immunogenic peptide GluR3B (amino-acid 372–395) to interact with and activate recombinant GluR3-receptor channels expressed by Xenopus oocytes. We report here that the affinity-purified anti-GluR3B Abs directly activate GluR3-containing homomeric and heteromeric AMPA receptor complexes without the requirement of neuronal, glial or blood ancillary molecules. We present some of the properties of the purified anti-GluR3B Abs and discuss the possible physiological or pathological consequences of their activation of glutamate receptors.