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Electrophysiological Endophenotypes of Schizophrenia in Mouse and Man

Award Number: R01MH093450
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/26/2012
PERIOD OF PERFORMANCE END DATE: 03/31/2021

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Electrophysiological Endophenotypes of Schizophrenia in Mouse and Man - DESCRIPTION (provided by applicant): Development of new drug therapies for CNS disorders has significantly lagged behind other indication areas, with some estimates suggesting only a 1% success rate for new chemical entities in the United States. Factors contributing to this problem include: lack of disease-relevant functional screens, lack of clinically predictive animal models and absence of reliable and specific biomarkers of disease state. These challenges have particularly impacted the discovery of cognitive therapies for schizophrenia. The cognitive impairments in schizophrenia comprise a core and debilitating component of the illness for which there are currently no effective therapies. Development of animal models that can reliably mirror human cognition is challenging, since the cognitive capacities and behavioral repertoires of animals and humans are fundamentally distinct. One approach to bridging this gap is to define specific aspects of neural activity that are altered in the human disease state and in cognate animal models, and to include such measures in testing candidate drug efficacy. The power of this approach is that it takes advantage of phylogenetic conservation at the level of neural networks to translate directly between species. For example, in accord with previous reports noting a severe dysfunction in the ability of cortical networks to mount coherent gamma oscillations in schizophrenia patients, we have observed alterations in gamma oscillations in the calcineurin knockout (CNKO) and phencyclidine- mediated mouse models of schizophrenia. We observed significant modulation of gamma oscillations in the prefrontal cortex of mice during mnemonic tasks associated with novelty recognition/detection that is impaired in these mouse disease models. In an initial study aimed at identifying human equivalencies of this novelty- related neural activity, we have observed similar changes in gamma oscillations within frontal cortex during a novelty oddball task in a small population of healthy volunteers. These data provide support for the potential utility of neurophysiological endophenotypes within defined neural circuits as objective measures of cognitive disease states that can be translated from animal models to human patients. We propose to identify and validate cortical neurophysiological endophenotypes in both humans and mice that are associated with analogous cognitive behavioral tasks and similarly affected by disease state. A coordinated and reciprocal approach will be applied since human studies have the advantage of direct disease relevance, while rodent systems can provide higher resolution electrophysiological measures and can be manipulated via genetic and pharmacological means to test specific disease hypotheses. We propose that identified electrophysiological endophenotypes of the disease condition that are conserved between rodents and man will provide objective biomarkers for schizophrenia disease state and for assessing drug candidate efficacy during clinical trials, as well as diagnostic tools for personalization of optimal treatment regimes for patients. The research outlined in this proposal thus stands to benefit the large population of patients with schizophrenia and related illnesses.


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: 2021 ( Subtotal = -$3,795 )
2021	2016	EPHYSBIO LLC	41 LOWER COLLEGE RD FORGARTY HALL, 3RD FLOOR	KINGSTON	RI	02881	WASHINGTON	USA	Mental Health Research Grants	000	6	9/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$3,795
														Subtotal = -$3,795

Issue Date FY: 2020 ( Subtotal = -$328,304 )
2020	2016	EPHYSBIO LLC	41 LOWER COLLEGE RD FORGARTY HALL, 3RD FLOOR	KINGSTON	RI	02881	WASHINGTON	USA	Mental Health Research Grants	001	6	8/20/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2015	GALENEA CORP.	300 TECHNOLOGY SQ STE 2	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	4	5/14/2020	NON-COMPETING CONTINUATION	-$328,304
														Subtotal = -$328,304

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	EPHYSBIO LLC	135 FERRY RD	BRISTOL	RI	02809	BRISTOL	USA	Mental Health Research Grants	001	6	8/22/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$235,779
2018	2016	GALENEA CORP.							Mental Health Research Grants	000	5	8/22/2018	EXTENSION WITH OR WITHOUT FUNDS	-$235,779
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $561,808 )
2016	2016	GALENEA CORPORATION	790 MEMORIAL DRIVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	5	5/19/2016	EXTENSION WITH OR WITHOUT FUNDS	$561,808
														Subtotal = $561,808

Issue Date FY: 2015 ( Subtotal = $576,919 )
2015	2015	GALENEA CORPORATION	790 MEMORIAL DRIVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	4	6/11/2015	NON-COMPETING CONTINUATION	$576,919
														Subtotal = $576,919

Issue Date FY: 2014 ( Subtotal = $563,678 )
2014	2014	GALENEA CORPORATION	790 MEMORIAL DRIVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	3	8/5/2014	NON-COMPETING CONTINUATION	$563,678
														Subtotal = $563,678

Issue Date FY: 2013 ( Subtotal = $575,438 )
2013	2013	GALENEA CORPORATION	790 MEMORIAL DRIVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	2	5/22/2013	NON-COMPETING CONTINUATION	$575,438
														Subtotal = $575,438

Issue Date FY: 2012 ( Subtotal = $625,924 )
2012	2012	GALENEA CORPORATION	790 MEMORIAL DRIVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	1	7/26/2012	NEW	$625,924
														Subtotal = $625,924

Grand Total All Awards = $2,571,668

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Electrophysiological Endophenotypes of Schizophrenia in Mouse and Man

Award Number: R01MH093450

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/26/2012

PERIOD OF PERFORMANCE END DATE: 03/31/2021

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