# AMPAR Function in Synaptic and Extrasynaptic Membranes

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $423,055

## Abstract

AMPA receptors (AMPARs) mediate the majority of excitatory glutamatergic synaptic transmission in the
central nervous system. Most AMPARs, once bound to glutamate, allow Na+ and K+ flux across the cell
membrane, causing neurons to depolarize. However, AMPARs that lack the GluR2 subunit are also permeable
to Ca2+. These Ca2-permeable (CP) AMPARs are highly expressed during development when they are
essential for activity-dependent plasticity, and this function persists at some synapses throughout adulthood. A
biophysical characteristic known as rectification is commonly used to differentiate CP-AMPARs from Ca2+-impermeable (CI) AMPARs. Whereas CP-AMPARs exhibit strong inward rectification, CI-AMPA receptors
display linear current-voltage relationships. Inward rectification of CP-AMPARs results from intracellular
polyamines that act as open channel blockers to prevent outward current flux. Thus, inward rectification and
sensitivity to antagonists that bind at the polyamine site provide biophysical signatures of AMPAR subunit
composition and hence Ca2+ permeability, and these characteristics have been widely used to establish rules
of AMPAR subunit plasticity. Molecular layer interneurons of the cerebellum provide a well-established model
system for understanding AMPAR localization and trafficking because repetitive synaptic stimulation or a single
experience of fear triggers a form of plasticity called subunit-switching wherein CP-AMPARs at synapses are
replaced by CI-AMPARs from a pool of extrasynaptic AMPARs. Although rectification index and sensitivity to
polyamine site toxins are widely used to distinguish between GluR2-containing and -lacking AMPARs, there
are many examples from the literature that show these biophysical properties do not exclusively reflect subunit
composition. A separate literature has converged on gating models of AMPARs that include multiple
conductance states, but the functional implications are unclear. Now, our preliminary data show that CP-AMPAR rectification and pharmacology are sensitive to factors that regulate AMPAR conductance states,
potentially complicating the interpretation of results using these biophysical properties as sole proxies of
subunit composition. We propose to understand how the multiple sub-conductance states of AMPARs
contribute to the hallmark biophysical properties CP-AMPARs. We will use high resolution Ca2+ imaging,
heterologous expression systems and genetic manipulation to understand regulation of CP-AMPAR
biophysical properties and use that understanding to critically evaluate CP-AMPAR localization and plasticity in
cerebellar molecular layer interneurons.
AMPAR subunit composition has important functional consequences,
ranging from regulating the ability of postsynaptic cells to precisely follow high-frequency synaptic activity and
mediating Ca2+ influx that can trigger plasticity or pathology. Successful completion of the proposed studies will
reveal novel properties of AMPARs that are es...

## Key facts

- **NIH application ID:** 10640949
- **Project number:** 5R01NS113948-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Jacques Wadiche
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $423,055
- **Award type:** 5
- **Project period:** 2019-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10640949

## Citation

> US National Institutes of Health, RePORTER application 10640949, AMPAR Function in Synaptic and Extrasynaptic Membranes (5R01NS113948-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10640949. Licensed CC0.

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