# Molecular dissection of synaptic dysfunction in mental disorders

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2021 · $467,766

## Abstract

Genetic analyses of polygenic brain disorders, such as autism spectrum disorders (ASDs) and schizophrenia
(SZ), have revealed “synaptic dysfunction” as a key cellular substrate for these disorders. Yet, translating this
synaptic hypothesis to in vitro disease modeling and extracting disease-relevant biological information has
been challenging. The PI has previously established a human neuronal model of SZ, combining isogenic
genome engineering, patient-derived induced pluripotent stem cells (iPSCs), and induced neuronal
differentiation (iN cells). Human neurons bearing mutations in the synaptic cell adhesion molecule Neurexin-1
(NRXN1, 2p16.3), a bona fide risk allele for SZ, display deficits in excitatory synaptic strength and
neurotransmitter release probability as well as a consistent upregulation of calcium/calmodulin-dependent
serine protein kinase (CASK) protein level, by which the mechanism is currently not understood. It remains
unclear how these phenotypes arise and lead to synaptic pathology and abnormal neuronal networks
implicated in the disease. In this grant, we aim to understand the cell type- and developmental-specific
functions of NRXN1-CASK interaction in normal synapse development and their mechanistic contributions to
SZ. Using synaptic molecules as a proxy, we will dissect how disruptions in the synaptic pathway can prime or
actively participate in SZ. We will achieve this by studying aberrant CASK signaling in NRXN1 mutant
background (Aim 1), investigating CASK’s normal function at human synapses using CASK KO induced
neurons (Aim 2) and by revealing key cellular events mediated by NRXN1 and CASK during human forebrain
development using KO cortical spheroid models (Aim 3). Our work integrates techniques in imaging,
electrophysiology, biochemistry and single cell RNA-seq with rigorous experimental designs using isogenic
engineered and patient-derived iPSCs from multiple genetic and gender backgrounds, differentiation of pure
induced neuronal subtypes with defined synaptic characteristics and differentiation of 3-D cortical spheroids
with characterized cellular features. Findings of this grant will provide mechanistic understanding of the
molecular and cellular underpinnings of neuropsychiatric disorders and such information will translate to other
disorders of the synapse, including intellectual disability, ASDs, and bipolar and mood disorders.

## Key facts

- **NIH application ID:** 10136112
- **Project number:** 5R01MH122519-02
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Changhui Pak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $467,766
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136112

## Citation

> US National Institutes of Health, RePORTER application 10136112, Molecular dissection of synaptic dysfunction in mental disorders (5R01MH122519-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136112. Licensed CC0.

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