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Cellular mechanisms of GABAergic inhibition in neocortical dendrites

Award Number: R01MH099045
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2012
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Cellular mechanisms of GABAergic inhibition in neocortical dendrites - SUMMARY The development, function, and plasticity of GABAergic circuits in the neocortex are critical processes for establishing and maintaining normal patterns of brain activity. Moreover, the dysregulation of GABA signaling is implicated in a number of neuropsychiatric disorders, including schizophrenia and autism. The majority of studies on GABAergic transmission have focused on fast, phasic signals that inhibit target neurons, negatively controlling postsynaptic integration and spike generation. However, GABA can also act via tonic currents that provide a steady-state influence on postsynaptic cells. While tonic GABA largely has been assumed to negatively regulate neuronal activity, recent data from our lab suggests that it may paradoxically enhance excitability of dendrites in cortical pyramidal neurons. Whether this unexpected observation extends throughout the somatodendritic arbor and across cell types is unknown. Additionally, the source of GABA producing tonic currents remains poorly understood, though evidence suggests it may include the same interneurons mediating phasic inhibition. In the present study, we propose a combination of electrophysiology, 2-photon imaging, pharmacology, and optogenetic manipulation both in acute brain slices and in vivo to (1) determine how tonic GABA currents shape dendritic excitability throughout the arbors of cortical pyramidal neurons, (2) identify the neuronal sources of GABA mediating tonic currents in the neocortex, and (3) determine the molecular mechanisms underlying long-term heterosynaptic plasticity of tonic GABAergic signals. Our overall goal is to understand the links between GABAergic transmission and cortical circuit function. We expect that our results will generate new avenues for exploring both the cell biology and functional consequences of GABAergic signaling in the cortex.


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 = $0 )
2026	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	12	11/19/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $610,779 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	12	6/17/2025	COMPETING CONTINUATION	$610,779
														Subtotal = $610,779

Issue Date FY: 2024 ( Subtotal = -$412 )
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	10	4/4/2024	NON-COMPETING CONTINUATION	-$412
														Subtotal = -$412

Issue Date FY: 2022 ( Subtotal = $418,362 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	10	10/22/2021	NON-COMPETING CONTINUATION	$376,525
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	10	5/12/2022	NON-COMPETING CONTINUATION	$41,837
														Subtotal = $418,362

Issue Date FY: 2021 ( Subtotal = $418,362 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	9	5/11/2021	NON-COMPETING CONTINUATION	$41,837
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	9	10/28/2020	NON-COMPETING CONTINUATION	$376,525
														Subtotal = $418,362

Issue Date FY: 2020 ( Subtotal = $585,846 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	8	11/8/2019	NON-COMPETING CONTINUATION	$376,525
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	8	2/3/2020	NON-COMPETING CONTINUATION	$41,837
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	002	8	7/21/2020	SUPPLEMENT FOR EXPANSION	$167,484
														Subtotal = $585,846

Issue Date FY: 2019 ( Subtotal = $418,362 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	7	10/24/2018	NON-COMPETING CONTINUATION	$418,362
														Subtotal = $418,362

Issue Date FY: 2018 ( Subtotal = $418,362 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	6	11/11/2017	COMPETING CONTINUATION	$418,362
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	003	6	4/13/2018	COMPETING CONTINUATION	$327,306
2018	2016	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	5	12/8/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
2018	2016	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	002	5	4/13/2018	EXTENSION WITH OR WITHOUT FUNDS	-$327,306
														Subtotal = $418,362

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	5	12/21/2016	EXTENSION WITH OR WITHOUT FUNDS	$375,470
2017	2015	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	4	12/21/2016	NON-COMPETING CONTINUATION	-$375,470
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $416,250 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	5	7/9/2016	EXTENSION WITH OR WITHOUT FUNDS	$416,250
														Subtotal = $416,250

Issue Date FY: 2015 ( Subtotal = $416,250 )
2015	2015	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	4	8/27/2015	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2014 ( Subtotal = $616,250 )
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Mental Health Research Grants	002	2	4/28/2014	SUPPLEMENT FOR EXPANSION	$200,000
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Mental Health Research Grants	003	3	8/7/2014	NON-COMPETING CONTINUATION	$416,250
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	2	4/15/2014	SUPPLEMENT FOR EXPANSION	-$200,000
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	2	3/28/2014	SUPPLEMENT FOR EXPANSION	$200,000
														Subtotal = $616,250

Issue Date FY: 2013 ( Subtotal = $399,600 )
2013	2013	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	2	8/26/2013	NON-COMPETING CONTINUATION	$399,600
														Subtotal = $399,600

Issue Date FY: 2012 ( Subtotal = $415,208 )
2012	2012	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	1	9/20/2012	NEW	$415,208
														Subtotal = $415,208

Grand Total All Awards = $5,133,219

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Cellular mechanisms of GABAergic inhibition in neocortical dendrites

Award Number: R01MH099045

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2012

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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