# Protein phosphatase 1 isoforms, human de novo mutations and synaptic functions

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $574,981

## Abstract

Reversible phosphorylation is a critical regulatory mechanism for spine morphogenesis, synaptic
transmission, long-term potentiation (LTP) and memory formation. Protein phosphatase 1 (PP1) contributes to
almost half of the serine/threonine phosphorylation in the mammalian cells, however, the role of three different
PP1 isoforms (PP1α, β, γ) in these processes is ill defined.
 PP1β is not believed to play a role in CNS function. On the other hand, whether PP1α and PP1γ play a role
in synaptic functions have never been determined directly. By using conditional knockout mouse models, we
found that PP1β inhibits synaptic transmission and spine maturation while promotes LTP induction and memory
formation. On the other hand, we found that PP1γ increases synaptic transmission, with PP1α compensating
PP1γ.
 The overarching hypothesis of this application is that myosin phosphatase targeting 1 (MYPT1) and neurabin
(Nrb) mediate the distinct effects of PP1β and PP1γ/α on synaptic function, respectively. In detail, we will test
our hypothesis in Aim 1 that PP1β-MYPT1 holoenzyme inhibits non-muscle myosin IIB-mediated F-actin
contraction in inhibiting spine maturation and synaptic transmission. We will determine in Aim 2 that PP1γ, in
combination with PP1α, promotes spine maturation, synaptic transmission by interaction with Nrb, a major
synaptic scaffolding protein. We will also test our prediction that PP1γ/α achieves these via dephosphorylating
Nrb at Ser200. In Aim 3 we will test our prediction that PP1β inhibits LTD induction, promotes LTP induction and
memory formation while PP1γ/α plays an opposite role.
 We will determine the structure-synaptic function relationship in the roles of PP1β in synaptic transmission
and plasticity, with an emphasis on PP1β C-termini in which one of the human PP1β de novo mutations resides.
 These studies will provide signaling mechanisms of, and structure determinants on, PP1 isoforms in
regulating their distinct roles on synaptic functions.

## Key facts

- **NIH application ID:** 10809672
- **Project number:** 5R01MH128279-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** HOUHUI XIA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $574,981
- **Award type:** 5
- **Project period:** 2023-03-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809672

## Citation

> US National Institutes of Health, RePORTER application 10809672, Protein phosphatase 1 isoforms, human de novo mutations and synaptic functions (5R01MH128279-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10809672. Licensed CC0.

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