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Understanding the Impact of CACNA1A/unc-2 Mutations on Presynaptic Structure and Function in C. Elegans

Award Number: F31NS137667
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/15/2025
PERIOD OF PERFORMANCE END DATE: 02/14/2027

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Understanding the Impact of CACNA1A/unc-2 Mutations on Presynaptic Structure and Function in C. Elegans - Project Summary/Abstract Mutations in the gene CACNA1A, which encodes Cav2.1, the a1 subunit of P/Q type voltage gated calcium channels, lead to severely debilitating channelopathies. Patients are classically diagnosed with syndromes such as episodic ataxia type 2 (EA2) or familial hemiplegic migraine type 1 (FHM1), though some patients also exhibit intellectual disability (ID) or multiple overlapping symptoms. Prior studies have largely focused on studying biophysical properties of these channels in heterologous systems or on mouse models of loss-of-function (LOF) EA2 mutations that have been linked to aberrant cerebellar Purkinje cell pacemaking. FHM1 has been associated with gain-of-function (GOF) effects leading to overexcitation and cortical spreading depression. Recent studies have suggested that in vitro characterization often obscures more complex or neuronal compartment specific effects in vivo. Cav2.1 plays a prominent role at presynaptic terminals to drive vesicular neurotransmitter release, yet the synaptic effects of many mutations remain understudied. Moreover, the molecular mechanisms that underlie patient symptoms beyond FHM1 and EA2, such as cognitive dysfunction are unknown. The overarching purpose of this proposal is to interrogate how two uncharacterized CACNA1A mutations associated with ID in patients alter synaptic transmission and lead to circuit-wide defects, comparing their effects on synaptic function to more well-characterized LOF and GOF mutations. The nematode C. elegans will be used to model patient-derived mutations in vivo, taking advantage of this powerful genetic system. C. elegans have a single CACNA1A orthologue, unc-2, which displays significant homology to the mammalian channel. The Kurshan lab has thus far generated five mutant CACNA1A/unc-2 strains, modeling either EA2, FHM1, or non-syndromic mutations that lead to ID. Aim 1 of this proposal will determine how synaptic function is altered in these mutant strains by measuring synaptic vesicle release using established and novel behavioral assays, performing electrophysiological recordings, and imaging channel expression in different cell types. Aim 2 will use molecular cloning techniques, calcium imaging and optogenetics to dissect the neural circuits impacted by the mutations, as well as a forward genetic screen to identify additional components of the signaling pathways mediating aberrant circuit output. Completion of this study will lead to a better understanding of the molecular perturbations caused by ID-associated CACNA1A/unc-2 mutations and work to identify synaptic targets for therapeutic intervention to treat patients suffering from these neurological disorders. This proposal will greatly enhance the F31 candidate’s scientific and professional development through strong mentorship and fantastic support from the Albert Einstein College of Medicine, while also leading towards their goal of becoming an independent investigator.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/10/2026	NON-COMPETING CONTINUATION	$576
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/13/2026	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/5/2024	NEW	$48,974
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	8/11/2025	NEW	$564
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/5/2024	NEW	$0
														Subtotal = $49,538

Grand Total All Awards = $99,652

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Understanding the Impact of CACNA1A/unc-2 Mutations on Presynaptic Structure and Function in C. Elegans

Award Number: F31NS137667

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/15/2025

PERIOD OF PERFORMANCE END DATE: 02/14/2027

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