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Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits

Award Number: R01NS110742
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits - The diversity of information encoding by neuronal circuits is regulated by the magnitude and location of Ca2+ entry though voltage-gated Ca2+ channels (CaV). In the mammalian central nervous system, the CaV2.1 channel is the critical subtype for CNS function since it is the most efficient CaV2 subtype at triggering synaptic vesicle (SV) release. At the majority of synapses, CaV2.1 is present at higher levels and in closest proximity to SVs. During development synapses become progressively more dependent on CaV2.1 due to selective reduction of CaV2.2 and CaV2.3. Neurons that signal with rapid and temporally precise action-potentials use Cav2.1 exclusive synapses that have fast SV release kinetics. Additionally, CaV2.1 is the dominant CaV2 isoform associated with human CaV2 channelopathies that manifest in migraine, epilepsy, and ataxia. Consistent with these findings, dysregulation of SV release is a cause of these and several other neurological disorders. Despite the importance of CaV2.1 in CNS function, we know little about the molecular mechanisms that regulate these CaV2.1 functions at the synapse. The calyx of Held, a glutamatergic presynaptic terminal in the auditory brainstem utilizes rapid and temporally precise action potential signaling for encoding information. The calyx undergoes a developmental change from having multiple CaV2 subtypes to CaV2.1 exclusively. Since it is the sole input to drive post-synaptic action potential spiking and due to the ability to directly measure presynaptic Ca2+ currents and correlate them to SV release rate, the calyx is an exceptional model for gaining mechanistic insights into the presynaptic regulation of SV release and neuronal circuit output. We will use transgenic mouse models and novel viral vectors to manipulate CaV2 subtypes at the calyx during different developmental stages. With these tools and proposed experiments, we will determine how the CaV2 α1 subunit regulates CaV2 subtype levels, organization and proximity to SVs thereby controlling synaptic transmission and neuronal circuit output. Given the importance of CaV2 channels in regulating synaptic transmission, as well as the pathological consequences of aberrant SV release, we envision that our findings will provide fundamental insights into how information is encoded by the nervous system, facilitating the development of treatments for a wide range of neurological and neuropsychiatric disorders.


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: 2025 ( Subtotal = -$151,409 )
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/5/2025	NON-COMPETING CONTINUATION	$183,928
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/1/2025	NON-COMPETING CONTINUATION	-$183,928
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	6/11/2025	NON-COMPETING CONTINUATION	-$151,409
														Subtotal = -$151,409

Issue Date FY: 2024 ( Subtotal = $358,976 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/3/2024	NON-COMPETING CONTINUATION	$25,905
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/17/2023	NON-COMPETING CONTINUATION	$333,071
														Subtotal = $358,976

Issue Date FY: 2023 ( Subtotal = $370,077 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/1/2023	NON-COMPETING CONTINUATION	$37,006
2023	2023	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/23/2022	NON-COMPETING CONTINUATION	$333,071
														Subtotal = $370,077

Issue Date FY: 2022 ( Subtotal = $385,434 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/20/2022	NON-COMPETING CONTINUATION	$38,541
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/11/2021	NON-COMPETING CONTINUATION	$346,893
														Subtotal = $385,434

Issue Date FY: 2021 ( Subtotal = $385,434 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/6/2021	NON-COMPETING CONTINUATION	$38,541
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/13/2020	NON-COMPETING CONTINUATION	$346,893
														Subtotal = $385,434

Issue Date FY: 2020 ( Subtotal = $385,434 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/18/2019	NEW	$385,434
														Subtotal = $385,434

Grand Total All Awards = $1,733,946

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Presynaptic regulation of neurotransmitter release in mammalian neuronal circuits

Award Number: R01NS110742

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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