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Effect of GABAergic inhibition of dendritic spines on synaptic pruning in the medial prefrontal cortex during adolescence

Award Number: R01MH115900
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Dendritic spines undergo synaptic pruning in the medial prefrontal cortex (mPFC) during adolescence, a process which is excessive in schizophrenia, believed to underlie cognitive impairment. Despite its importance, the mechanism underlying synaptic pruning in the mPFC is not known. Our preliminary findings suggest that extrasynaptic a4ßd GABAA receptors (GABARs), which transiently emerge on the spine at puberty onset (~PND 35) for 10d, trigger adolescent synaptic pruning in the mPFC. These receptors generate a shunting inhibition which impairs NMDA receptor activation. Our previous findings in CA1 hippocampus established that the inhibition generated by these receptors reduces expression of the Rho-GEF spine protein Kalirin-7, necessary for spine maintenance, via this reduced NMDA receptor activity. We will test the hypothesis that similar effects on spine proteins play a role in adolescent pruning in mPFC. The proposed aims will use multiple techniques, including in vivo two-photon imaging, electrophysiological, pharmacological, and immunocytochemical assays. To this end, we will chronically manipulate a4ßd function during adolescence (~PND 35-44) and quantify spine density at 8 and 12 wks of age. Preliminary data shows that spine density is decreased in both layer 3 and 5 post- pubertally in +/+ but not a4-/- mice, implicating a4ßd GABARs. Because synaptic GABAergic input targets the spine in the cortex, the role of a1ß2¿2 GABARs will also be examined. These experiments will use acute pharmacological (agonists, modulators) and genetic manipulation (global/conditional/local knock-down) of a4ßd and a1ß2¿2 to explore the role of these receptors in regulating spine density and morphology assessed using Golgi and electrophysiological techniques. To explore the effect of this pruning on circuit and behavioral plasticity, in vivo two-photon techniques in combination with multi- neuron recording will be used to image the Ca++ signals and record activity generated by neuronal ensembles in response to visual stimuli in the awake mouse across adolescence and after GABAR modulation/knock-down. We will thus assess the effect of pubertal a4ßd GABARs and GABAR- generated pruning on circuit function, including the power and synchronization of theta and gamma oscillations as well as on circuit activity/synchronization of ensembles and mPFC-dependent learning tasks. The findings from the proposed studies will directly address the functional role of GABAergic inhibition on dendritic spines at puberty, and will also provide mechanisms for the process of synaptic pruning, as well as explore functional outcomes of alterations in this process. These results are relevant for schizophrenia where excessive synaptic pruning and impaired working memory are reported in association reduced power/sychronization of visually-evoked gamma oscillations, and where single nucleotide polymorphisms of the d gene are reported, suggesting a genetic link.


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: 2023 ( Subtotal = $629,227 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	000	5	11/2/2022	NON-COMPETING CONTINUATION	$566,305
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	001	5	2/21/2023	NON-COMPETING CONTINUATION	$62,922
														Subtotal = $629,227

Issue Date FY: 2022 ( Subtotal = $629,227 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	001	4	5/13/2022	NON-COMPETING CONTINUATION	$62,922
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	000	4	11/4/2021	NON-COMPETING CONTINUATION	$566,305
														Subtotal = $629,227

Issue Date FY: 2021 ( Subtotal = $629,227 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	001	3	4/13/2021	NON-COMPETING CONTINUATION	$62,922
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	000	3	10/28/2020	NON-COMPETING CONTINUATION	$566,305
														Subtotal = $629,227

Issue Date FY: 2020 ( Subtotal = $647,762 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	001	2	2/3/2020	NON-COMPETING CONTINUATION	$64,775
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	000	2	11/11/2019	NON-COMPETING CONTINUATION	$582,987
														Subtotal = $647,762

Issue Date FY: 2019 ( Subtotal = $689,713 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Mental Health Research Grants	000	1	12/6/2018	NEW	$689,713
														Subtotal = $689,713

Grand Total All Awards = $3,225,156

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Effect of GABAergic inhibition of dendritic spines on synaptic pruning in the medial prefrontal cortex during adolescence

Award Number: R01MH115900

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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