AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

Evidence from neuropathological, genetic, animal model, and biochemical studies has indicated that the accumulation of amyloid-beta (Aβ) is associated with, and probably induces, profound neuronal changes in brain regions critical for memory and cognition in the development of Alzheimer’s disease (AD). There is considerable evidence that synapses are particularly vulnerable to AD, establishing synaptic dysfunction as one of the earliest events in pathogenesis, prior to neuronal loss. It is clear that excessive Aβlevels can disrupt excitatory synaptic transmission and plasticity, mainly due to dysregulation of the AMPA and NMDA glutamate receptors in the brain. Importantly, AMPA receptors are the principal glutamate receptors that mediate fast excitatory neurotransmission. This is essential for synaptic plasticity, a cellular correlate of learning and memory, which are the cognitive functions that are most disrupted in AD. Here we review recent advances in the field and provide insights into the molecular mechanisms that underlie Aβ-induced dysfunction of AMPA receptor trafficking. This review focuses primarily on NMDA receptor- and metabotropic glutamate receptor-mediated signaling. In particular, we highlight several mechanisms that underlie synaptic long-term depression as common signaling pathways that are hijacked by the neurotoxic effects of Aβ.

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AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2013.15.1/jhenley ◽

2013 ◽

Vol 15 (1) ◽

pp. 11-27 ◽

Cited By ~ 25

Keyword(s):

Synaptic Plasticity ◽

Ampa Receptor ◽

Ampa Receptors ◽

Cognitive Aging ◽

Postsynaptic Membrane ◽

Receptor Trafficking ◽

Brain Diseases ◽

Excitatory Transmission ◽

Age Related ◽

Ampa Receptor Trafficking

Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs are highly dynamic proteins that are subject to highly controlled trafficking, recycling, and/or degradation and replacement. This active regulation of AMPAR synthesis, targeting, synaptic dwell time, and degradation is fundamentally important for memory formation and storage. Further, aberrant AMPAR trafficking and consequent detrimental changes in synapses are strongly implicated in many brain diseases, which represent a vast social and economic burden. The purpose of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and highlight what is known currently known about how these processes change with age and disease.

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Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation

Science Signaling ◽

10.1126/scisignal.abb1953 ◽

2021 ◽

Vol 14 (670) ◽

pp. eabb1953

Author(s):

Luís F. Ribeiro ◽

Tatiana Catarino ◽

Mário Carvalho ◽

Luísa Cortes ◽

Sandra D. Santos ◽

...

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Receptor Trafficking ◽

Excitatory Synapses ◽

Ghrelin Receptor ◽

Term Potentiation ◽

Ghrelin Receptors ◽

Ampa Receptor Trafficking

The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser845. Reducing the ligand-independent activity of GHS-R1a increased the surface diffusion of AMPA receptors and impaired AMPA receptor–dependent synaptic delivery induced by chemical long-term potentiation. Accordingly, we found that blocking this GHS-R1a activity impaired spatial and recognition memory in mice. These observations support a role for the ligand-independent activity of GHS-R1a in regulating AMPA receptor trafficking under basal conditions and in the context of synaptic plasticity that underlies learning.

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Faculty Opinions recommendation of Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1008084.102108 ◽

2002 ◽

Author(s):

Vladimir I Gelfand

Keyword(s):

Ampa Receptor ◽

Receptor Trafficking ◽

Myosin Vi ◽

Actin Motor ◽

Ampa Receptor Trafficking

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PKMζ maintains memories by regulating GluR2-dependent AMPA receptor trafficking

Nature Neuroscience ◽

10.1038/nn.2531 ◽

2010 ◽

Vol 13 (5) ◽

pp. 630-634 ◽

Cited By ~ 179

Author(s):

Paola Virginia Migues ◽

Oliver Hardt ◽

Dong Chuan Wu ◽

Karine Gamache ◽

Todd Charlton Sacktor ◽

...

Keyword(s):

Ampa Receptor ◽

Receptor Trafficking ◽

Ampa Receptor Trafficking

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Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

Translational Psychiatry ◽

10.1038/s41398-021-01289-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daniela Lichtman ◽

Eyal Bergmann ◽

Alexandra Kavushansky ◽

Nadav Cohen ◽

Nina S. Levy ◽

...

Keyword(s):

Social Behavior ◽

Functional Connectivity ◽

Mouse Model ◽

Ampa Receptor ◽

Social Preference ◽

Autism Spectrum ◽

Receptor Trafficking ◽

Anterior Cingulate ◽

The Impact ◽

Ampa Receptor Trafficking

AbstractIQSEC2 is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure–function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

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