The study of synaptic plasticity and specifically LTP and LTD is one of the most active areas of research in neuroscience. In the last 25 years we have come a long way in our understanding of the ...mechanisms underlying synaptic plasticity. In 1988, AMPA and NMDA receptors were not even molecularly identified and we only had a simple model of the minimal requirements for the induction of plasticity. It is now clear that the modulation of the AMPA receptor function and membrane trafficking is critical for many forms of synaptic plasticity and a large number of proteins have been identified that regulate this complex process. Here we review the progress over the last two and a half decades and discuss the future challenges in the field.
Studies of LTP and LTD have been models for how the combination of classic electrophysiology and molecular methodologies can open the door for mechanistic insights into neuronal function. Rick Huganir and Roger Nicoll review the recent history and debates around the mechanisms of LTP and LTD and future directions for the field.
Changes in the properties and postsynaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity, including long-term potentiation ...(LTP), long-term depression (LTD), and homeostatic scaling. The function and the trafficking of AMPARs to and from synapses is modulated by specific AMPAR GluA1–GluA4 subunits, subunit-specific protein interactors, auxiliary subunits, and posttranslational modifications. Layers of regulation are added to AMPAR tetramers through these different interactions and modifications, increasing the computational power of synapses. Here we review the reliance of synaptic plasticity on AMPAR variants and propose “the AMPAR code” as a conceptual framework. The AMPAR code suggests that AMPAR variants will be predictive of the types and extent of synaptic plasticity that can occur and that a hierarchy exists such that certain AMPARs will be disproportionally recruited to synapses during LTP/homeostatic scaling up, or removed during LTD/homeostatic scaling down.
Changes in the number and properties of postsynaptic AMPARs are a fundamental mechanism of synaptic plasticity. Diering and Huganir discuss how AMPAR subunits, posttranslational modifications, and protein binding partners form combinatorial molecular codes relevant for understanding synapse function and plasticity.
SynGAP is a Ras-GTPase activating protein highly enriched at excitatory synapses in the brain. Previous studies have shown that CaMKII and the RAS-ERK pathway are critical for several forms of ...synaptic plasticity including LTP. NMDA receptor-dependent calcium influx has been shown to regulate the RAS-ERK pathway and downstream events that result in AMPA receptor synaptic accumulation, spine enlargement, and synaptic strengthening during LTP. However, the cellular mechanisms whereby calcium influx and CaMKII control Ras activity remain elusive. Using live-imaging techniques, we have found that SynGAP is rapidly dispersed from spines upon LTP induction in hippocampal neurons, and this dispersion depends on phosphorylation of SynGAP by CaMKII. Moreover, the degree of acute dispersion predicts the maintenance of spine enlargement. Thus, the synaptic dispersion of SynGAP by CaMKII phosphorylation during LTP represents a key signaling component that transduces CaMKII activity to small G protein-mediated spine enlargement, AMPA receptor synaptic incorporation, and synaptic potentiation.
Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous ...cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95. Binding of SynGAP to PSD-95 induces phase separation of the complex, forming highly concentrated liquid-like droplets reminiscent of the PSD. The multivalent nature of the SynGAP/PSD-95 complex is critical for the phase separation to occur and for proper activity-dependent SynGAP dispersions from the PSD. In addition to revealing a dynamic anchoring mechanism of SynGAP at the PSD, our results also suggest a model for phase-transition-mediated formation of PSD.
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•SynGAP forms a coiled-coil trimer, and each binds to two molecules of PSD-95•SynGAP/PSD-95 complex undergoes liquid-liquid-phase separation•SynGAP/PSD-95 phase separation suggests a possible PSD formation mechanism•Phase-separation-mediated SynGAP PSD enrichment is correlated with synaptic activity
The interaction between two major components of postsynaptic densities induces phase separation of the newly formed complex into liquid-like droplets, suggesting a mechanism for the formation and activity-dependent modulation of synaptic complexes.
Traumatic fear memories can be inhibited by behavioral therapy for humans, or by extinction training in rodent models, but are prone to recur. Under some conditions, however, these treatments ...generate a permanent effect on behavior, which suggests that emotional memory erasure has occurred. The neural basis for such disparate outcomes is unknown. We found that a central component of extinction-induced erasure is the synaptic removal of calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) in the lateral amygdala. A transient up-regulation of this form of plasticity, which involves phosphorylation of the glutamate receptor 1 subunit of the AMPA receptor, defines a temporal window in which fear memory can be degraded by behavioral experience. These results reveal a molecular mechanism for fear erasure and the relative instability of recent memory.
SynGAP is a potent regulator of biochemical signaling in neurons and plays critical roles in neuronal function. It was first identified in 1998, and has since been extensively characterized as a ...mediator of synaptic plasticity. Because of its involvement in synaptic plasticity, SynGAP has emerged as a critical protein for normal cognitive function. In recent years, mutations in the
gene have been shown to cause intellectual disability in humans and have been linked to other neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia. While the structure and biochemical function of SynGAP have been well characterized, a unified understanding of the various roles of SynGAP at the synapse and its contributions to neuronal function remains to be achieved. In this review, we summarize and discuss the current understanding of the multifactorial role of SynGAP in regulating neuronal function gathered over the last two decades.
Bidirectional synaptic plasticity occurs locally at individual synapses during long-term potentiation (LTP) or long-term depression (LTD), or globally during homeostatic scaling. LTP, LTD, and ...homeostatic scaling alter synaptic strength through changes in postsynaptic AMPA-type glutamate receptors (AMPARs), suggesting the existence of overlapping molecular mechanisms. Phosphorylation controls AMPAR trafficking during LTP/LTD. We addressed the role of AMPAR phosphorylation during homeostatic scaling. We observed bidirectional changes of the levels of phosphorylated GluA1 S845 during scaling, resulting from a loss of protein kinase A (PKA) from synapses during scaling down and enhanced activity of PKA in synapses during scaling up. Increased phosphorylation of S845 drove scaling up, while a knockin mutation of S845, or knockdown of the scaffold AKAP5, blocked scaling up. Finally, we show that AMPARs scale differentially based on their phosphorylation status at S845. These results show that rearrangement in PKA signaling controls AMPAR phosphorylation and surface targeting during homeostatic plasticity.
•Synaptic PKA activity and phosphorylation of AMPARs is altered during scaling•AKAP5 and GluA1 S845 are required for homeostatic scaling up•AMPA receptors scale differentially based on their phosphorylation state•The effect of neuromodulators and NMDAR activation are altered during scaling
The relationship between Hebbian plasticity and homeostatic scaling is not known. The PKA signaling pathway is a key regulator of homeostatic scaling and suggests how global plasticity can occur while being sensitive to local or prior signaling at individual synapses.
Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many ...symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.
Sleep is an essential process that supports learning and memory by acting on synapses through poorly understood molecular mechanisms. Using biochemistry, proteomics, and imaging in mice, we find that ...during sleep, synapses undergo widespread alterations in composition and signaling, including weakening of synapses through removal and dephosphorylation of synaptic AMPA-type glutamate receptors. These changes are driven by the immediate early gene Homer1a and signaling from group I metabotropic glutamate receptors mGluR1/5. Homer1a serves as a molecular integrator of arousal and sleep need via the wake- and sleep-promoting neuromodulators, noradrenaline and adenosine, respectively. Our data suggest that homeostatic scaling-down, a global form of synaptic plasticity, is active during sleep to remodel synapses and participates in the consolidation of contextual memory.
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