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Linking mitochondrial and synaptic weakness to schizophrenia

Award Number: R01MH136706
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/19/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Linking mitochondrial and synaptic weakness to schizophrenia - Schizophrenia (SZ) is a heterogenous neurodevelopmental disorder in which the complex and interacting influences of genetics and environment drive neuropathological processes leading to symptom development. While the precise neuropathological underpinnings of SZ remain undetermined, and multiple brain regions are likely to be involved, both genetic and neuropathological evidence suggest that disrupted glutamatergic synaptic function in the cerebral cortex can be an important component of symptom development in SZ. Studies, including from the contact PI Stewart Anderson’s, lab have also suggested that mitochondrial weakness may contribute to the development of schizophrenia. Since a major locus, perhaps the major locus, of mitochondrial ATP dependence for neural function occurs in the presynaptic terminal, it stands to reason that mitochondrial weakness could be one influencer of the glutamatergic synaptic disruption contributing to SZ. The most common genetic risk factor for SZ is the 22q11.2 deletion syndrome (22qDS), occurring in about 1:3000 births, roughly one quarter of which develop SZ. We previously used IPSC-derived glutamatergic neurons (iNeurons) and lymphoblastoid cell lines to demonstrate that while the condition of 22q+SZ is associated with weaker ATP production via oxidative phosphorylation (OXPHOS), 22qDS without SZ (22q(-)SZ) is associated with elevated levels of mitochondrial-biogenesis related transcripts that may denote a compensatory mechanism reducing SZ risk. Treatment of iNeurons from the 22q+SZ group with the medication bezafibrate resulted in enhanced expression of mitochondria biogenesis-related genes as well as normalization of their ATP production. Here we propose to extend these studies with the following aims: Aim 1: Study of mitochondrial biogenesis and mitophagy in IPSC-derived neurons from 22qDS with or without SZ and unaffected controls. We hypothesize that there will be enhanced mitochondrial biogenesis and turnover in the 22q(-)SZ group relative to both controls and 22q+SZ. Aim 2: Study of glutamatergic synaptic release in IPSC-derived neurons from 22qDS with or without SZ and unaffected controls. We hypothesize that OXPHOS deficits in IPSC-derived neurons from 22qDS+SZ will result in reduced glutamatergic synaptic release and reduced synaptic vesicle cycling relative to neurons from 22qDS without schizophrenia and to healthy controls, and that activation of mitochondrial biogenesis with bezafibrate will normalize synaptic vesicle cycling and glutamate release in the 22qDS+SZ group. Success in showing that 22q(-)SZ is associated with enhanced mitochondrial biogenesis/turnover would bolster the rationale for targeting this system to prevent or ameliorate SZ symptoms in 22qDS. Since synaptic energetic weakness, potentially interacting with genetic and environmental factors that also affect synaptic function, has been implicated in non-syndromic SZ and other neuropsychiatric disorders, the novel human-based experimental paradigms we apply in this proposal could be broadly applicable to other IPSC-based studies of brain disease.


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 = $649,499 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	1/21/2026	NON-COMPETING CONTINUATION	$649,499
														Subtotal = $649,499

Issue Date FY: 2025 ( Subtotal = $649,499 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	2	9/23/2025	NON-COMPETING CONTINUATION	$97,425
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	2	1/23/2025	NON-COMPETING CONTINUATION	$552,074
														Subtotal = $649,499

Issue Date FY: 2024 ( Subtotal = $651,279 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	1	7/18/2024	NEW	$651,279
														Subtotal = $651,279

Grand Total All Awards = $1,950,277

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Linking mitochondrial and synaptic weakness to schizophrenia

Award Number: R01MH136706

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/19/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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