# Protein phosphatase 1 isoforms and human de novo mutations in synaptic plasticity

> **NIH NIH F30** · UNIVERSITY OF ROCHESTER · 2022 · $51,752

## Abstract

PROJECT SUMMARY
Synaptic plasticity presents a cellular model for learning and memory and provides a framework to study
cognitive deficits in neurological disorders. Protein phosphatase 1 (PP1) is a major regulator of synaptic plasticity
that acts directly on synaptic and nuclear substrates involved in synaptic plasticity, including AMPA receptors
and CREB, respectively. There are three neuronal isoforms of PP1 with different but overlapping subcellular
localizations and substrates. Each PP1 isoform is highly expressed in the hippocampus, but their distinct
functions have not been studied. Rather, the isoforms have been grouped together in classic studies that use
pharmacologic or peptide inhibition of PP1.
PP1α and PP1γ1 are assumed to be the primary isoforms regulating synaptic plasticity due to their enrichment
in the dendritic spine and interactions with major scaffolding proteins, whereas PP1β, found primarily in the
dendritic shaft and soma, is believed to play a minor role. Surprisingly, human de novo mutations were recently
discovered in PP1β that cause intellectual disability and autism-like behaviors.
Using a genetic knockout approach with floxed transgenic mice, I investigated the effect of knocking out individual
PP1 isoforms on synaptic transmission and plasticity in the hippocampus, at Schaffer collateral-CA1. My
preliminary data suggest a novel role for PP1β that opposes PP1γ1, while PP1α plays a minor, redundant role.
Additionally, my preliminary data demonstrates a role of PP1 in regulating basal synaptic transmission, which is
otherwise obscured by classic pharmacological approaches. In this project, I will replicate and expand these
findings using several approaches: electrophysiology, immunoblotting, morphological analysis, and imaging.
In Aim 1, I will investigate the role of each PP1 isoform in regulating synaptic transmission and plasticity using
our floxed transgenic mice, which allow for PP1 isoform-specific knockout. In Aim 2, I will determine the effect
of human de novo PP1β mutations on synaptic transmission and plasticity using a genetic replacement
approach, in which one copy of wildtype PP1β is replaced with mutated PP1β, as in affected human patients.
Completion of this project will provide me with the knowledge base and technical skills necessary to pursue a
successful career as a physician-scientist in neurology. Moreover, these findings will inform our understanding
of the molecular mechanisms of synaptic plasticity and their connection to intellectual disability.

## Key facts

- **NIH application ID:** 10333322
- **Project number:** 5F30MH122046-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Karl Francis Wilson Foley
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333322

## Citation

> US National Institutes of Health, RePORTER application 10333322, Protein phosphatase 1 isoforms and human de novo mutations in synaptic plasticity (5F30MH122046-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10333322. Licensed CC0.

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