# Neuronal Adaptation and Plasticity after Chronic Disuse

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $625,433

## Abstract

ABSTRACT
Homeostatic regulation of excitability and synaptic efficacy works in conjunction with acutely induced Hebbian
plasticity to maintain neuron firing within limits and thus preserve network stability and information flow. There
is general agreement that homeostatic plasticity can affect intrinsic properties (action potential duration
controlling neurotransmission) or synaptic properties (unitary synaptic current amplitude, for example) and
involves diverse molecular mechanisms. Dysfunctional homeostasis has been invoked as a basis for brain
diseases such as autism spectrum disorders (ASD). Despite major effort, the molecular underpinnings of
various forms of homeostatic adaptation are still not clear. In this project, we will examine various aspects of
neuronal homeostasis with relevance to neuropsychiatric disorders. The first question is how neuronal
inactivity initiates local signaling near postsynaptic CaV1 channels and causes propagation of signals to the
nucleus to regulate alternative mRNA splicing (AS) and thus affect spike duration. We will extend our findings
on how one ASD-related gene (CACNA1C, L-type Ca2+ channel subunit) controls the expression of another
(KCNMA1, BK channel subunit). Our data suggest that signaling to the nucleus via bCaMKK (encoded by
CAMKK2) plays a critical role in AS through effects on localization of the splice factor Nova-2. In another
subproject, we will clarify how the same activity silencing affects synaptic properties, and the striking
switchover of postsynaptic glutamate receptors from Ca2+-impermeable to Ca2+-permeable AMPA receptors.
We will decipher how various signaling pathways, generating both negative and positive feedback, work in
coordination to trigger a damped oscillatory response of synaptic properties following TTX silencing, a novel
observation from our group. We will take studies of homeostasis to recurrent circuits in cultured hippocampal
slices, using an all-optical approach to visualize reallocation of presynaptic weights following inactivity and their
postsynaptic consequences. Each of the Aims are of relevance to disease states such as ASD and
schizophrenia. Using a mouse model of Timothy Syndrome, a rare form of ASD, we will probe how
physiological phenomena are altered in a pathogenic setting, for example exploring why inactivity-driven BK
splicing is much more severe in Timothy Syndrome neurons and probing how this affects higher order
functions of relevance to ASD.

## Key facts

- **NIH application ID:** 9974167
- **Project number:** 2R01MH071739-17
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** RICHARD W TSIEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $625,433
- **Award type:** 2
- **Project period:** 2004-07-16 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974167

## Citation

> US National Institutes of Health, RePORTER application 9974167, Neuronal Adaptation and Plasticity after Chronic Disuse (2R01MH071739-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974167. Licensed CC0.

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