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.

Public Health Relevance

Synaptic strength must be regulated in the face of changing levels of input in order to ensure that neurons are able to maintain their output firing within reasonable limits. Homeostatic regulation of action potential duration and synaptic efficacy works in conjunction with acutely induced Hebbian plasticity to maintain network stability and information flow. This project will study the features and mechanisms of adaptation to chronic disuse aiming to advance our understanding of how cells remodel themselves, and shed light on abnormal responses in disease states, including autism spectrum disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH071739-17
Application #
9974167
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Kim, Douglas S
Project Start
2004-07-16
Project End
2025-01-31
Budget Start
2020-04-01
Budget End
2021-01-31
Support Year
17
Fiscal Year
2020
Total Cost
Indirect Cost
Name
New York University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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