# SynDIG1/Prrt1 regulation of extrasynaptic GluA1-containing AMPARs during plasticity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $83,139

## Abstract

ABSTRACT
Activity-dependent variation in synaptic AMPA receptor (AMPAR) content, referred to as ‘synaptic plasticity’, is
a mechanism whereby information is stored in neural networks that give rise to higher order cognitive skills
such as learning and memory. During long-term potentiation (LTP), a widely studied form of synaptic plasticity,
extrasynaptic AMPARs are recruited from nearby reserve pools, including perisynaptic regions on the cell
surface and intracellular compartments, and subsequent anchored with the postsynaptic density (PSD). A large
body of evidence spanning decades of investigation has established mechanisms by which AMPARs are
anchored within the PSD. In contrast, the molecular mechanisms that govern AMPAR synaptic targeting to
establish reserve pools of extrasynaptic receptors are largely unknown. Given that recruitment of reserve pools
of extrasynaptic AMPARs underlies the rapid strengthening of synapses that occurs during LTP, the molecular
mechanisms that establish such reserve pools are critical to our understanding of synaptic plasticity and
represent a major gap in our knowledge.
SynDIG (Synapse Differentiation Induced Gene) defines a family of four genes (SynDIG1-4) that encode brain-
specific transmembrane proteins. Here we will determine the function of SynDIG4 (SD4), also known as Prrt1
(Proline-rich transmembrane protein 1) in the regulation of the reserve pool of AMPARs. Proteomic studies
indicate that SD4 is a component of AMPAR complexes; however, SD4 is not enriched in the PSD, but instead
colocalizes with GluA1-containing AMPARs at non-synaptic sites. Remarkably, tetanus-induced LTP, which is
dependent on GluA1, is abolished in acute hippocampal slices from SD4 knockout (KO) while theta-burst
stimulation LTP (TBS-LTP), which is independent of GluA1, is not impaired. Furthermore, SD4 KO mice exhibit
profound deficits in two independent cognitive assays (Morris water maze, novel object recognition),
demonstrating a critical role for SD4 in hippocampal-dependent learning and memory. Moreover, extrasynaptic
AMPARs are reduced in SD4 KO compared with wild-type (WT) neurons. Given that reserve pools of
extrasynaptic AMPARs are critical for synaptic plasticity, we hypothesize that SD4 maintains such reserve pools
of extrasynaptic GluA1-containing AMPARs that are deployed during tetanus-induced LTP.
In this collaborative dual-PI application we propose a comprehensive multidisciplinary approach to investigate
SD4-dependent regulation of extrasynaptic GluA1-containing AMPARs with molecular, cellular, and
electrophysiological methods. In Aim 1 we will define the mechanism by which SD4 maintains extrasynaptic
GluA1-containing AMPARs. In Aim 2 we will determine whether synaptic targeting of reserve pools of GluA1-
containing AMPARs during plasticity requires SD4. In Aim 3 we will test whether homomeric GluA1-dependent
synapse plasticity mechanisms require SD4 ex vivo at multiple ages. The results of these studies will prov...

## Key facts

- **NIH application ID:** 10693621
- **Project number:** 3R01MH119347-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** ELVA D DIAZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $83,139
- **Award type:** 3
- **Project period:** 2019-09-24 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693621

## Citation

> US National Institutes of Health, RePORTER application 10693621, SynDIG1/Prrt1 regulation of extrasynaptic GluA1-containing AMPARs during plasticity (3R01MH119347-04S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693621. Licensed CC0.

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