Synaptic AMPA receptor composition in development, plasticity and disease

Abstract

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

Coordination of AMPA receptor trafficking by Rab GTPases

“…It is now widely accepted that the amount and composition of AMPA receptors within the postsynaptic density (PSD) of dendritic spines determine synaptic efficacy and affect the excitability of the neuron (reviewed in ref. 13).…”

Hippocampal amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid GluA1 (AMPAGluA1) receptor subunit involves in learning and memory improvement following treatment withCentella asiaticaextract in adolescent rats

“…Approximately 80% of synaptic AMPARs in the CA1 hippocampal neurons consist of GluA1 and GluA2 heteromers. The GluA1 subunit is highly expressed in the hippocampus, central amygdala, and cerebellum (Anggono & Huganir, 2012; Henley & Wilkinson, 2016; Inta et al., 2014; Sanderson & Bannerman, 2012). These AMPARs are critically important for nearly all aspects of brain function, including learning, memory, and cognition, as they mediate the overwhelming majority of fast excitatory neurotransmission in the CNS (Henley & Wilkinson, 2013).…”

Learning about Synaptic GluA3

“…Long-term potentiation (LTP) and long-term depression (LTD) at glutamatergic synapses are extensively studied forms of long-lasting synaptic plasticity that are widely regarded as key mechanisms for learning and memory, and deficits in LTP and LTD are linked to many neurological and mental disorders, including intellectual disability, autism and Alzheimer disease (Henley and Wilkinson, 2016). Thus, the mechanisms governing these forms of plasticity are a subject of intensive investigation.…”

“…However, the extent to which these receptors, and their composite subunits, mediate these changes remains controversial (Huganir and Nicoll, 2013;Henley and Wilkinson, 2016).…”