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Excitability and Plasticity of Developing Epileptic Brain

Award Number: R01NS029709
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Excitability and Plasticity of Developing Epileptic Brain - Abstract Our long term goal is to learn how an inherited single gene error produces a specific pattern of epilepsy in the developing brain, to provide an exact description of relevant plasticity within affected neural networks, and to reverse the seizure phenotype at the earliest possible stage. Spike-wave (SW) absence seizures comprise a major category of inherited epilepsy in children, and often herald cognitive deficits and more severe seizures. Over 20 mutant genes for this phenotype are known, and their effects on channel behavior and routes of convergence on excitability within thalamocortical pacemaking circuitry are now more clearly defined. The P/Q calcium channel mouse mutant is a prototype for this analysis, and like other models, shows elevated thalamic T-type calcium currents that are sufficient to generate absence epilepsy, illuminating a shared downstream plasticity pathway triggered by functionally disparate upstream SW genes. The mechanism underlying T-type current remodeling is not understood. In the past project period we narrowed the critical pathogenic microcircuitry and found that selective ablation of P/Q type calcium channels in Layer 6 corticothalamic neurons alone are sufficient to elevate thalamic T currents and cause SW epilepsy, reducing the analysis from the entire brain to a single thalamic afferent synapse, and showed that adult P/Q channel deletion reproduces the childhood syndrome albeit through an alternative pattern of T current circuit remodeling. Using newly created models, we will 1) analyze native and alternative thalamic transcriptome changes to define the molecular basis for T current plasticity in thalamic excitatory and inhibitory neurons and uncover novel epistatic genes participating in this switch, 2) test the thalamic current imbalance in a digenic model to simulate the combinatorial effects of common human CAE variants in T currents, and 3) determine whether we can reverse the T current imbalance and epileptic phenotype in PQ channel mutants by restoring normal PQ function after the onset of seizures. This analysis brings us closer to molecular level treatments of pathogenic gene expression in epilepsy.


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: 2024 ( Subtotal = $416,874 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	31	5/31/2024	NON-COMPETING CONTINUATION	$416,874
														Subtotal = $416,874

Issue Date FY: 2023 ( Subtotal = $429,766 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	30	5/25/2023	NON-COMPETING CONTINUATION	$429,766
														Subtotal = $429,766

Issue Date FY: 2022 ( Subtotal = $429,766 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	29	4/19/2022	NON-COMPETING CONTINUATION	$429,766
														Subtotal = $429,766

Issue Date FY: 2021 ( Subtotal = $359,743 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	28	6/21/2021	COMPETING CONTINUATION	$429,766
2021	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	27	2/1/2021	NON-COMPETING CONTINUATION	-$70,023
														Subtotal = $359,743

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	27	4/3/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $346,719 )
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	27	8/7/2018	NON-COMPETING CONTINUATION	$346,719
2018	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	26	8/6/2018	NON-COMPETING CONTINUATION	$0
2018	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	26	8/2/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $346,719

Issue Date FY: 2017 ( Subtotal = $346,719 )
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	26	8/9/2017	NON-COMPETING CONTINUATION	$346,719
														Subtotal = $346,719

Issue Date FY: 2016 ( Subtotal = $346,719 )
2016	2016	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	7/22/2016	NON-COMPETING CONTINUATION	$346,719
														Subtotal = $346,719

Issue Date FY: 2015 ( Subtotal = $346,719 )
2015	2015	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	24	8/21/2015	COMPETING CONTINUATION	$346,719
2015	2014	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	8/20/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $346,719

Issue Date FY: 2014 ( Subtotal = $473,618 )
2014	2014	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	3/20/2014	NON-COMPETING CONTINUATION	$473,618
														Subtotal = $473,618

Issue Date FY: 2013 ( Subtotal = $461,656 )
2013	2013	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	5/29/2013	NON-COMPETING CONTINUATION	$31,096
2013	2013	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	3/19/2013	NON-COMPETING CONTINUATION	$430,560
														Subtotal = $461,656

Issue Date FY: 2012 ( Subtotal = $478,400 )
2012	2012	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	3/26/2012	NON-COMPETING CONTINUATION	$478,400
														Subtotal = $478,400

Issue Date FY: 2011 ( Subtotal = $478,400 )
2011	2011	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	7/5/2011	COMPETING CONTINUATION	$478,400
														Subtotal = $478,400

Issue Date FY: 2010 ( Subtotal = $328,406 )
2010	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	11/19/2009	NON-COMPETING CONTINUATION	$295,313
2010	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	1/13/2010	NON-COMPETING CONTINUATION	$29,532
2010	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	19	7/6/2010	SUPPLEMENT FOR EXPANSION	$3,561
2010	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	19	7/19/2010	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $328,406

Issue Date FY: 2009 ( Subtotal = $328,125 )
2009	2009	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	18	4/13/2009	NON-COMPETING CONTINUATION	$32,812
2009	2009	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	11/14/2008	NON-COMPETING CONTINUATION	$295,313
														Subtotal = $328,125

Issue Date FY: 2008 ( Subtotal = $328,125 )
2008	2008	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	11/29/2007	NON-COMPETING CONTINUATION	$328,125
														Subtotal = $328,125

Issue Date FY: 2007 ( Subtotal = $328,125 )
2007	2007	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	1/24/2007	COMPETING CONTINUATION	$328,125
														Subtotal = $328,125

Issue Date FY: 2006 ( Subtotal = $338,015 )
2006	2006	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	12/1/2005	NON-COMPETING CONTINUATION	$338,015
														Subtotal = $338,015

Issue Date FY: 2005 ( Subtotal = $346,150 )
2005	2005	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	12/3/2004	NON-COMPETING CONTINUATION	$346,150
														Subtotal = $346,150

Issue Date FY: 2004 ( Subtotal = $396,150 )
2004	2004	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	11/11/2003	NON-COMPETING CONTINUATION	$346,150
2004	2004	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	7/26/2004	SUPPLEMENT FOR EXPANSION	$50,000
														Subtotal = $396,150

Grand Total All Awards = $9,089,254

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Excitability and Plasticity of Developing Epileptic Brain

Award Number: R01NS029709

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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