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Identifying Convergent Circuit Disruptions Across Genetically-Distinct Models of Autism

Award Number: R01HD111753
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Identifying Convergent Circuit Disruptions Across Genetically-Distinct Models of Autism - Identifying Convergent Circuit Disruptions Across Genetically-Distinct Rat Models of ASD Summary: Recent advances from human genetic and animal studies have greatly increased our understanding of the molecular and cellular basis of autism spectrum disorders (ASD). Connecting these risk factors to clinical symptoms in autism remains a significant challenge that has impeded the development of ASD therapies, as evidenced by disappointing results from recent large-scale clinical trials. A fundamental question is if distinct ASD mutations converge on shared disease mechanisms at some level of neuronal function to ultimately give rise to the behavioral and neurocognitive phenotypes that define autism. Identifying these pathophysiological convergence points is essential for developing treatment strategies that may generalize across genetically heterogenous forms of ASD. We have previously shown that rodent models of the two most common genetically-defined causes of autism— Fmr1 KO mouse model of Fragile X syndrome (FX) and Tsc2+/- mouse model of tuber sclerosis complex (TSC)— exhibit opposite synaptic and cellular phenotypes that responded to opposite pharmacological interventions, despite sharing a molecular pathway and presenting with similar behavioral phenotypes. This proposal will determine if Fmr1 and Tsc2 mutations converge on common circuit disruptions that can account for shared behavioral phenotypes in these disorders. We will address this question through the lens of the auditory system, as auditory processing impairments are a common and debilitating sensory phenotype in ASD that directly impacts communicative and social behavior while also providing robust and translationally-relevant behavioral and physiological read-outs, due to its well- characterized neuroanatomy and evolutionary conserved nature. Specifically, this proposal will test the hypothesis that circuit hyperexcitability due to altered excitatory/inhibitory synaptic balance and dysregulated parvalbumin expressing (PV+) interneuron function is a convergent disease mechanism that leads to shared deficits in auditory perception and information processing in rat models of FX and TSC. This will be accomplished by combining the unique behavioral advantaged of rat models with in vivo and ex vivo electrophysiological recordings, cell-type specific optogenetic manipulations, and molecular profiling techniques. Determining how Fmr1 and Tsc2 mutations lead to auditory processing deficits and neural circuit dysfunction will not only help identify novel therapies for disabling sensory phenotypes in these disorders, but may shed light on recurring pathophysiological motifs that generalize across neurocognitive domains and extend to diverse forms of ASD.


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: 2025 ( Subtotal = $418,076 )
2025	2025	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Child Health and Human Development Extramural Research	000	3	5/22/2025	NON-COMPETING CONTINUATION	$418,076
														Subtotal = $418,076

Issue Date FY: 2024 ( Subtotal = $408,494 )
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Child Health and Human Development Extramural Research	000	2	7/11/2024	NON-COMPETING CONTINUATION	$408,494
														Subtotal = $408,494

Issue Date FY: 2023 ( Subtotal = $424,896 )
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Child Health and Human Development Extramural Research	000	1	9/22/2023	NEW	$424,896
														Subtotal = $424,896

Grand Total All Awards = $1,251,466

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Identifying Convergent Circuit Disruptions Across Genetically-Distinct Models of Autism

Award Number: R01HD111753

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/22/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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