# Assessing Synaptic and Intrinsic Effects of Patient-Derived ID-Associated CACNA1A Mutations Using Multiple Models

> **NIH NIH R21** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $210,000

## Abstract

Abstract
Mutations in the CACNA1A gene, which encodes the pore-forming subunit of the P/Q type calcium
channel (Cav2.1), lead to neurological disorders including Episodic Ataxia type 2 (EA2) and Familial
Hemiplegic Migraine type 1 (FHM1). Patients have typically been classified as having one of these disorders or
the other, but symptoms are often overlapping and the distinction has been called into question. More recently,
CACNA1A patients presenting primarily with cognitive defects such as intellectual disability or developmental
delay have been described, suggesting that a more salient dichotomy may lie between mutations that lead to
severe motor deficits and those that are characterized primarily by cognitive dysfunction. Motor dysfunction
such as ataxia has been attributed to disruption of neuronal excitability and pacemaking function of cerebellar
Purkinje cells, where these channels are most highly expressed. In contrast, t he underlying mechanisms
leading to cognitive dysfunction remain unknown. However, Cav2.1 channels are also expressed throughout
the nervous system at presynaptic terminals where they mediate synaptic vesicle release. The varying
functional consequences of different CACNA1A mutations underscore the importance of delineating the impact
of each CACNA1A mutation on channel expression and function to understand how each causes the
associated disease phenotypes. We hypothesize that mutations that effect primarily neuronal excitability result
in classical motor phenotypes, while those that effect synaptic properties may give rise to cognitive deficits. To
begin to address this, we propose to characterize an array of CACNA1A patient mutations resulting in either
primarily motor or primarily cognitive presentations. We have validated and now propose to combine two model
systems to characterize the effect of these mutations: a heterologous expression system (HEK293t cells) to
assess cell-surface expression and biophysical properties using molecular, imaging, and whole cell
electrophysiology techniques, as well as the nematode C. elegans to investigate in vivo presynaptic
localization and synaptic function. This work will lay the foundation for elucidating the mechanism by which
CACNA1A mutations affect neuronal function and lead to pleiotropic patient outcomes.

## Key facts

- **NIH application ID:** 10819562
- **Project number:** 5R21NS132111-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** PERI T KURSHAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $210,000
- **Award type:** 5
- **Project period:** 2023-05-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819562

## Citation

> US National Institutes of Health, RePORTER application 10819562, Assessing Synaptic and Intrinsic Effects of Patient-Derived ID-Associated CACNA1A Mutations Using Multiple Models (5R21NS132111-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10819562. Licensed CC0.

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