Investigating TCF4 and synaptic dysfunction in pitt-hopkins syndrome

Active Project Grant Awarded Last action

Award ID
F31MH138091
Recipient
Awarding agency
Obligated
$128,286

Award facts

Assistance listing
93.242 Mental Health Research Grants
Completion date 59% complete
Place of performance
Baltimore, MD 21205, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Autism spectrum disorders (asds) present a complex array of neurodevelopmental challenges, affecting approximately 1 in 100 individuals globally. Despite substantial efforts to understand the genetic underpinnings of ASD, therapeutic treatments remain elusive. Transcription factor 4 (TCF4) loss-of-function (LOF) mutations are implicated in pitt-hopkins syndrome (pths), a syndromic form of ASD. While pths pathophysiology has been extensively studied in murine models, understanding TCF4 function within a human context is imperative. This proposal aims to utilize patient-derived induced pluripotent cells (hipscs) to model synaptic transmission, focusing on presynaptic regulatory roles of TCF4 and the therapeutic potential of RIMBP2 RE-expression. Our recently published data indicate significant deficits in spontaneous excitatory postsynaptic currents (sepscs) and network activity in pths hipsc-derived neurons, potentially stemming from presynaptic abnormalities. From our differential expression gene analysis, RIMBP2, a presynaptic organizer, emerged as the most significantly downregulated gene, with its RE-expression rescuing deficits in network synchronicity and sepsc frequency. In this study, i will explore the impact of TCF4 LOF on presynaptic release, subcellular protein localization, and ultrastructure, along with mechanism by which RIMBP2 rescues deficits. In aim 1, i will employ live-cell imaging with the glutamate sensor IGLUSNFR3 to quantify presynaptic release deficits and changes in evoked neurotransmitter release, release probability, and coupling distance between release ready vesicles and calcium channels. Additionally, with time-resolved electron microscopy, i will examine deficits in synaptic ultrastructure. In aim 2, i will characterize deficits involving calcium channel conductance, expression, and localization. First, i will measure presynaptic calcium influx with the calcium sensor syng-CAMP6F. Then, using quantitative microscopy, i will assess the expression and localization of calcium channels along with related proteins in the active zone. Finally, i will employ live-gold-labeling electron microscopy to measure the coupling distance between calcium channels and docked vesicles at the nanometer scale. The significance of this research lies in elucidating the synaptic deficits associated with TCF4 LOF, providing a foundation for targeted therapeutics. The anticipated results could identify candidate genes and inform novel approaches to restore presynaptic release deficits linked to TCF4 dysfunction in pths. The study's innovative methodology, incorporating advanced imaging techniques and human-derived models, contributes a unique perspective to understanding the synaptic architecture of neurons affected by TCF4 mutations. With the support of my proposed mentorship team and the outstanding training environment, the research and training activities proposed here will ideally position me for a future career in academic neuroscience research.

Transactions

Action Obligated Date
Amendment $0
Amendment $0
Amendment $43,138
Amendment $42,574
Amendment $42,574
Original award $0

Quick answers

Who received award F31MH138091?

F31MH138091 was awarded to Lieber Institute Inc. by National Institute of Mental Health (National Institutes of Health) on December 24, 2024.

How much is award F31MH138091 worth?

$128,286 has been obligated on F31MH138091.

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