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The Role of Hippocampal area CA2 in Epilepsy

Award Number: R01NS106983
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: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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The Role of Hippocampal area CA2 in Epilepsy - ABSTRACT A deeper understanding of the molecular, cellular, and circuit mechanisms that contribute to intractable epilepsy is of critical importance for improving existing therapeutic approaches. Rodent epilepsy models provide an important approach for achieving this goal and for the preclinical exploration of novel treatments. Here we focus on two types of mouse models relevant to drug-resistant seizure disorders in humans: the pilocarpine status epilepticus model (PILO-SE) of acquired temporal lobe epilepsy (TLE) and a mouse model with a genetic variant in voltage-gated ion channels that cause seizure disorders in humans. TLE shows a characteristic pattern of hippocampal neurodegeneration termed mesial temporal sclerosis (MTS), with substantial loss of pyramidal neurons in the CA1 and CA3 regions and a relative sparing of dentate gyrus (DG) and CA2 regions. Survival of DG and CA2 has led to the hypotheses that both are important for seizure activity. Although the role of DG has been well studied in rodent models, the role of CA2 has remained relatively unexplored. In the previous funding period, we found that PILO-SE leads to increased overall CA2 excitation, due to increased intrinsic excitability, enhanced synaptic excitation from DG and reduced synaptic inhibition. Importantly, we found that chronic chemogenetic or acute closed-loop optogenetic silencing of CA2 led to a significant decrease in seizure activity in PILO-SE mice. However, our previous analyses were restricted to dorsal CA2. We will address here the role of ventral CA2, as studies in both humans and rodent models suggest that ventral hippocampus may be an even more important site for seizures in TLE than dorsal hippocampus. We will therefore investigate the hypothesis that chemogenetic and/or optogenetic silencing of ventral CA2 will be even more effective in reducing seizures than observed upon silencing dorsal CA2. Our previous studies also left open the question as to whether the increase in CA2 excitation in PILO-SE is causally related to the role of CA2 in seizures. We will address this question by asking whether interventions that restore normal levels of CA2 intrinsic excitability can rescue seizures in PILO-SE. Such experiments have the advantage over genetic-based silencing as they will not interfere with the normal role of CA2 in hippocampal-dependent social memory. In addition to acquired forms of epilepsy, an increasing number of cases of epilepsy have been shown to be caused by genetic variants, some associated with MTS and others without MTS. Here we address whether CA2 may play a more general role in seizure activity by investigating its role in a mouse model of a genetic form of epilepsy caused by mutations in the gene encoding the HCN1 voltage-gated ion channel, and testing whether CA2 silencing can suppress seizures in this model. The experiments of this proposal thus offer the promise of further validating CA2 as target for novel therapeutic approaches for treatment of a range of seizure 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 = $578,735 )
2025	2025	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/30/2025	NON-COMPETING CONTINUATION	$578,735
														Subtotal = $578,735

Issue Date FY: 2024 ( Subtotal = $561,373 )
2024	2024	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	5/22/2024	NON-COMPETING CONTINUATION	$561,373
														Subtotal = $561,373

Issue Date FY: 2023 ( Subtotal = $594,710 )
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/29/2023	COMPETING CONTINUATION	$594,710
														Subtotal = $594,710

Issue Date FY: 2022 ( Subtotal = $527,555 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/20/2022	NON-COMPETING CONTINUATION	$527,555
														Subtotal = $527,555

Issue Date FY: 2021 ( Subtotal = $526,115 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/28/2021	NON-COMPETING CONTINUATION	$526,115
														Subtotal = $526,115

Issue Date FY: 2020 ( Subtotal = $524,203 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/19/2020	NON-COMPETING CONTINUATION	$524,203
														Subtotal = $524,203

Issue Date FY: 2019 ( Subtotal = $517,899 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/9/2019	NON-COMPETING CONTINUATION	$517,899
														Subtotal = $517,899

Issue Date FY: 2018 ( Subtotal = $473,382 )
2018	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/25/2018	NEW	$473,382
														Subtotal = $473,382

Grand Total All Awards = $4,303,972

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The Role of Hippocampal area CA2 in Epilepsy

Award Number: R01NS106983

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: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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