# Role of CACNA1C - a shared risk gene in neuropsychiatric disorders

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2020 · $94,544

## Abstract

Project 2: Role of CACNA1C – a shared risk factor in neuropsychiatric disorders
ABSTRACT
A major challenge in understanding human neuropsychiatric disorders has been the lack of viable tissues to
analyze. Patient-derived induced pluripotent stem cells (iPSC) now offer the opportunity to examine the full
complement of neural tissues and the prospect of identifying underlying disease mechanisms. Despite their
promise, “brain in a dish” models can be heterogeneous, masking similarities and subtle differences in
disease-related phenotypes. Systematic development and validation of cell-based assays relevant to
neuropsychiatric disease are therefore critically required. We are examining the effects of increased CACNA1C
expression associated with the AA allele of rs1006737 -- the strongest and most replicated association with
bipolar disorder (BP), and also implicated in schizophrenia (SZ) -- in neuronal differentiation and function.This
work builds on published investigations in which we have demonstrated a role for CACNA1C in neurogenesis
in animal models, and identified alterations in CACNA1C expression, calcium signaling, and neurotransmitter
release in neurons differentiated from BP patients compared with those from healthy controls (C). Remarkably,
lithium pre-treatment significantly reduced calcium transients and wave amplitude in BP neurons to control
levels, providing a tractable model system to identify prognostic tests and examine the response of iPSC-
derived neurons to pathway perturbagens and signaling networks suggested to be involved in BP. The
overarching goal of the research is to identify predictive tests that distinguish common and divergent
disease phenotypes and mechanisms in bipolar disorder and schizophrenia. The scientific hypothesis
for this project is that dysregulation of calcium signaling produces subtle but widespread alterations in
differentiation, plasticity and activity throughout the nervous system that influence susceptibility to
bipolar disorder. Using neurons derived from carriers of the AA allele of rs1006737 and cells from control
(GG allele) individuals, we will pursue three Specific Aims. Aim 1 will characterize the differentiation and
behaviors of glutamatergic cortical neurons, including neurite outgrowth, synaptic and dendritic behavior, and
mitochondrial status. Aim 2 will examine neuronal and network activity. Aim 3 will examine the differentiation of
astrocytes and GABAergic neurons, and the effects of normalizing CACNA1C expression on neural
differentiation in isogenic cell lines. These studies will directly test a long-standing theory regarding the role of
altered calcium signaling in mood disorders and will produce a set of validated protocols comparing DISC1
mutant and BP iPSC, with high throughput analyses to identify novel mechanisms and signaling relevant to
neuropsychiatric disease.

## Key facts

- **NIH application ID:** 10247959
- **Project number:** 3U19MH106434-05S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** K Sue Sue O'SHEA
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $94,544
- **Award type:** 3
- **Project period:** 2016-08-17 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247959

## Citation

> US National Institutes of Health, RePORTER application 10247959, Role of CACNA1C - a shared risk gene in neuropsychiatric disorders (3U19MH106434-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247959. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*