ATP P2X Receptors Downregulate AMPA Receptor Trafficking and Postsynaptic Efficacy in Hippocampal Neurons

AbstractParkinson’s disease (PD)-associated E3 ubiquitin ligase Parkin is enriched at glutamatergic synapses, where it ubiquitinates multiple substrates, suggesting that its mutation/loss-of-function could contribute to the etiology of PD by disrupting excitatory neurotransmission. Here, we evaluate the impact of four common PD-associated Parkin point mutations (T240M, R275W, R334C, G430D) on glutamatergic synaptic function in hippocampal neurons. We find that expression of these point mutants in Parkin-deficient and -null backgrounds alters NMDA and AMPA receptor-mediated currents and cell-surface levels, and prevents the induction of long-term depression. Mechanistically, we demonstrate that Parkin regulates NMDA receptor trafficking through its ubiquitination of GluN1, and that all four mutants are impaired in this ubiquitinating activity. Furthermore, Parkin regulates synaptic AMPA receptor trafficking via its binding and retention of the postsynaptic scaffold Homer1, and all mutants are similarly impaired in this capacity. Our findings demonstrate that pathogenic Parkin mutations disrupt glutamatergic synaptic transmission and plasticity by impeding NMDA and AMPA receptor trafficking, and through these effects likely contribute to the pathophysiology of PD inPARK2patients.

Download Full-text

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.

Download Full-text

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

Download Full-text

Faculty Opinions recommendation of PICK1 mediates transient synaptic expression of GluA2-lacking AMPA receptors during glycine-induced AMPA receptor trafficking.

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

10.3410/f.717970994.793469387 ◽

2013 ◽

Author(s):

Johannes Hell

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

Receptor Trafficking ◽

Ampa Receptor Trafficking

Download Full-text

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

Download Full-text

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.

Download Full-text