# RGS14 regulation of synaptic plasticity in hippocampal neurons

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $369,664

## Abstract

SUMMARY: RGS14 is a multifunctional signaling protein that integrates G protein, MAPkinase, and
calcium/CaM signaling pathways. RGS14 is found in brain where it is highly enriched in dendrites and spines
of pyramidal neurons in hippocampal region CA2. We discovered that RGS14 is critically important as a natural
suppressor of synaptic plasticity (long-term potentiation, LTP) in CA2 neurons. Our studies show that ectopic
delivery of RGS14 to CA1 neurons where RGS14 is not expressed blocks LTP there, suggesting that RGS14
engages common signaling pathways that are critical for synaptic plasticity in both populations of neurons.
Unlike CA1 neurons, little is known about CA2 neurons where RGS14 is expressed. This enigmatic brain region
has been implicated in social behavior and human neuro-psychological diseases including schizophrenia, the
autism/bipolar disorders, and epilepsy. Remarkably, we have found that mice lacking RGS14 (RGS14-KO)
exhibit an unexpected enhancement of spatial learning and object recognition memory compared with wild type
littermates, with no differences in non-hippocampal-dependent behaviors. Furthermore, RGS14-KO mice
expressed a surprisingly robust nascent LTP with enhanced neuronal excitability at glutamatergic synapses in
CA2, with no impact on plasticity in adjacent CA1 neurons. Together, these findings highlight the importance
of understanding the molecular mechanism(s) whereby RGS14 regulates LTP and synaptic plasticity within CA2
hippocampal neurons. LTP and associated spine plasticity depends on a rise in postsynaptic calcium due to
glutamate activation of NMDA/GluN channels and the voltage-gated calcium channel Cav1.2, which result in
activation of CaM and CaMKII signaling pathways. These pathways, in turn, increase actomyosin-driven
trafficking and insertion of AMPA/GluA receptor vesicles at the synapse that result in increased spine size (i.e.
structural plasticity). Of note, we find that RGS14 suppresses the activity-induced rise in spine calcium, inhibits
Cav1.2, binds Ca++/CaM, and is phosphorylated by CaMKII. Furthermore, we find that RGS14 suppresses spine
structural plasticity associated with LTP, and exists in brain as part of a high-molecular weight complex enriched
with spine myosins (MyoV, MyoVI, MyoII) and actin binding proteins. Based on these observations, our
working hypothesis is that RGS14 suppresses spine calcium by inhibiting Cav1.2 channels, and blocks LTP by
engaging the actomyosin system (in a regulated way) to limit surface AMPA receptors. We further propose that
these actions of RGS14 are regulated by its binding partners CaM, CaMKII, H-Ras/Rap2-GTP and Gai1. To test
these ideas, we propose the following experiments. AIM 1. Determine how Ca++/CaM binding and CaMKII
phosphorylation modulate established RGS14 functions. AIM 2: Determine how RGS14 regulates Cav1.2
and suppresses postsynaptic calcium signaling in hippocampal neurons. AIM 3: Determine how RGS14
impacts AMPA receptor recycling and...

## Key facts

- **NIH application ID:** 10183337
- **Project number:** 5R01NS037112-21
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** JOHN R HEPLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $369,664
- **Award type:** 5
- **Project period:** 1997-12-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183337

## Citation

> US National Institutes of Health, RePORTER application 10183337, RGS14 regulation of synaptic plasticity in hippocampal neurons (5R01NS037112-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10183337. Licensed CC0.

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