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Mitochondrial Dysfunction In Schizophrenia

Award Number: R01MH085801
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2009
PERIOD OF PERFORMANCE END DATE: 11/30/2021

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Mitochondrial Dysfunction In Schizophrenia - DESCRIPTION (provided by applicant): Mitochondria provide nearly all of the energy for synaptic transmission, maintenance of ionic homeostasis in synaptic terminals, development of neuronal spines, and long term potentiation which are all essential for brain function. In addition to these neuronal roles, mitochondria regulate cell survival, react to oxidative stressors, and provide ATP for most cellular functions. It is estimated that a single cortical neuron utilizes 109 molecules of ATP each second. In our initial grant, we found strong evidence of mitochondria dysfunction in schizophrenia, compared to weaker evidence for dysfunction in bipolar disorder. We conservatively estimated mitochondria DNA content heritability (h2 = 0.37), and found a highly significant decrease of mitochondria DNA in schizophrenia compared to controls and bipolar disorder. Our studies have also shown decreased gene expression and common deletion, in schizophrenia, but not in bipolar disorder, compared to controls. We have postulated a polygenic model that nuclear and mitochondrial genes interact to alter mitochondria content in periphery and in brain. This decrease in mitochondria in brain, could account for significant decreases in density of spines, especially prominent in layer III. We will further test this model, that mtDNA content is heritable, and under genetic control. We will also test association of mtDNA content with symptoms of schizophrenia. Since our initial studies have been conducted in chronic subjects with schizophrenia, we are renewing our grant to study subjects with first episode psychosis for evidence of the mitochondria dysfunction before onset of antipsychotic drug treatments. The overarching hypothesis is that the pathophysiology of SZ is associated with a reduction in mitochondrial function specifically in the localization and copy number of mitochondria in dendrite and axon locations compared to controls. The cause of the dysfunction postulated in our model is polygenic variation in both nuclear and mitochondrial genes that contribute to mitochondria copy number trait and function. We will test for association of mitochondria DNA copy number in both nuclear and mitochondrial SNPs in first episode psychosis and chronic psychosis, using blood and postmortem brain, and extend our investigations of postmortem brain to medication free individuals with schizophrenia, including bipolar disorder subjects for specificity of findings. To be confident that chronic treatment with antipsychotic drugs (APDs) does not alter mitochondria localization, we propose to study a cohort of non-human primate brains at cellular resolution, already chronically treated with APDs. Since synaptic terminal activity is dependent upon mitochondria function, we will compare the numbers of mitochondria located in postsynaptic spines in individuals with schizophrenia and controls, and APD treated rhesus monkeys compared to controls. Finally, we will assess whether APD treatment alters mitochondrial copy number, intraneuronal motility, and membrane potential in fibroblast-induced pluripotent stem cells reprogrammed into neurons from first episode psychosis subjects compared to controls. The outcomes of this study will expand our knowledge of genetic basis for mitochondria dysfunction in schizophrenia, and association of that dysfunction with psychiatric symptoms.


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: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	000	10	5/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $576,155 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Mental Health Research Grants	000	10	1/8/2020	NON-COMPETING CONTINUATION	$576,155
														Subtotal = $576,155

Issue Date FY: 2019 ( Subtotal = $598,931 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Mental Health Research Grants	000	9	1/24/2019	NON-COMPETING CONTINUATION	$598,931
														Subtotal = $598,931

Issue Date FY: 2018 ( Subtotal = $618,332 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Mental Health Research Grants	001	8	6/15/2018	NON-COMPETING CONTINUATION	$61,834
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Mental Health Research Grants	000	8	11/29/2017	NON-COMPETING CONTINUATION	$556,498
														Subtotal = $618,332

Issue Date FY: 2017 ( Subtotal = $618,332 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Mental Health Research Grants	001	7	5/9/2017	NON-COMPETING CONTINUATION	$61,834
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Mental Health Research Grants	000	7	11/30/2016	NON-COMPETING CONTINUATION	$556,498
														Subtotal = $618,332

Issue Date FY: 2016 ( Subtotal = $739,479 )
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	000	6	12/15/2015	COMPETING CONTINUATION	$677,948
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	001	6	2/20/2016	COMPETING CONTINUATION	$61,531
														Subtotal = $739,479

Issue Date FY: 2013 ( Subtotal = $363,528 )
2013	2013	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	000	5	4/12/2013	NON-COMPETING CONTINUATION	$340,808
2013	2013	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	001	5	6/10/2013	NON-COMPETING CONTINUATION	$22,720
														Subtotal = $363,528

Issue Date FY: 2012 ( Subtotal = $378,675 )
2012	2012	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	000	4	3/15/2012	NON-COMPETING CONTINUATION	$378,675
														Subtotal = $378,675

Issue Date FY: 2011 ( Subtotal = $378,675 )
2011	2011	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	000	3	3/11/2011	NON-COMPETING CONTINUATION	$344,250
2011	2011	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	001	3	6/29/2011	NON-COMPETING CONTINUATION	$34,425
														Subtotal = $378,675

Issue Date FY: 2010 ( Subtotal = $382,500 )
2010	2010	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	000	2	3/26/2010	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2009 ( Subtotal = $382,500 )
2009	2009	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Mental Health Research Grants	000	1	6/17/2009	NEW	$382,500
														Subtotal = $382,500

Grand Total All Awards = $5,037,107

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Mitochondrial Dysfunction In Schizophrenia

Award Number: R01MH085801

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2009

PERIOD OF PERFORMANCE END DATE: 11/30/2021

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