# Regulation of Calcium-permeable AMPA Receptors by AKAP79 Postsynaptic Signaling

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $432,494

## Abstract

Learning and memory requires multiple forms of synaptic plasticity mediated by mGlu, NMDA, AMPA
glutamate receptors (mGluR, NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation
(LTP) and long-term depression (LTD), that rapidly increase or decrease synaptic strength of specific inputs, and
homeostatic synaptic scaling, which scale-up or -down strength of all inputs. Importantly, alterations in
LTP/LTD and homeostatic plasticity are associated with cognitive dysfunction in animal models of nervous
system disorders. Until recently, the signaling mechanisms controlling AMPARs during LTP/LTD and
homeostatic plasticity were envisioned as distinct. However, LTP/LTD and homeostatic plasticity can both
result in synaptic incorporation of high-conductance, Ca2+-permeable AMPA receptors (CP-AMPAR) containing
GluA1, but lacking GluA2, subunits that not only impact synaptic strength but also alter plasticity itself - i.e.
metaplasticity. Nevertheless, the roles of CP-AMPARs in controlling plasticity in hippocampal neurons are
controversial. A major barrier to moving the field forward has been that we do not have an adequate
understanding of the signaling mechanisms that control CP-AMPARs. Importantly, recent studies from our
laboratory employing knock-in mice demonstrated that the kinase PKA and phosphatase Calcineurin (CaN)
anchored to A-kinase anchoring protein (AKAP) 79/150 play opposing roles regulating GluA1 phosphorylation
to control both basal and plasticity-regulated CP-AMPAR synaptic incorporation at hippocampal synapses. In
particular, we found that AKAP-PKA/CaN positive/negative regulation of CP-AMPAR synaptic incorporation
controls LTP/LTD balance and determines whether synapses can undergo homeostatic potentiation. In
addition, we found that palmitoylation/depalmitoylation of the AKAP N-terminal targeting domain controls AKAP
delivery/removal from dendritic spines in coordination with cellular correlates of LTP/LTD. Furthermore, recent
unpublished work indicates that knock-in disruption of AKAP palmitoylation in vivo increases basal CP-AMPAR
activity to prevent subsequent LTP. Finally, both published and unpublished data indicate that these CP-
AMPAR-mediated changes in plasticity are influenced by developmental age, induction stimulus, and crosstalk
with CaMKII and mGlu1 signaling suggesting engagement of metaplasticity. Here we will use the unique
knock-in mice we developed to test the overall hypothesis that regulation of AKAP postsynaptic targeting by
palmitoylation (aim 1) and CaMKII signaling (aim 2), and interactions between AKAP-PKA/CaN and mGluR
signaling (aim 3) control LTP/LTD balance at CA1 synapses through CP-AMPAR-mediated metaplasticity.

## Key facts

- **NIH application ID:** 9919646
- **Project number:** 5R01NS040701-18
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MARK L DELL'ACQUA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,494
- **Award type:** 5
- **Project period:** 2001-08-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919646

## Citation

> US National Institutes of Health, RePORTER application 9919646, Regulation of Calcium-permeable AMPA Receptors by AKAP79 Postsynaptic Signaling (5R01NS040701-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9919646. Licensed CC0.

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