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Sex-specific mechanisms of cortical circuit dysfunction in a mouse ASD model

Award Number: R37NS114516
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Sex-specific mechanisms of cortical circuit dysfunction in a mouse ASD model - Increasing evidence indicates that Autism Spectrum Disorder (ASD) is manifests differently in males and females behaviorally and affects brain function and connectivity differently between sexes. There has been little known of how ASD genes affect the female brain on a cellular and microcircuit level. During the previous grant period we discovered that deletion of the ASD-risk gene, Pten (Phosphatase and tensin homolog deleted on chromosome 10), in neocortical pyramidal neurons (NSEPten KO) resulted in robust hyperexcitability of local neocortical circuits in female, but not male, mice, observed as prolonged, spontaneous persistent activity states (UP states). We also demonstrated that circuit hyperexcitability in NSEPten KO mice is mediated by enhanced signaling of metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) to ERK and de novo protein synthesis selectively in Pten deleted female neurons. Pten deleted Layer 5 cortical neurons have a female-specific increase in mGluR5 levels and mGluR5-driven protein synthesis. In addition, mGluR5-ERα complexes are elevated in female cortex and genetic reduction of ERα in Pten KO cortical neurons rescues circuit excitability, protein synthesis and enhanced neuron size selectively in females. Abnormal timing and hyperexcitability of neocortical circuits in female NSEPten KO mice are associated with deficits in temporal processing of sensory stimuli and social behaviors as well as mGluR5-dependent seizures. Female-specific cortical hyperexcitability and mGluR5-dependent seizures are also observed in a human disease relevant mouse model, germline Pten+/- mice. Our results demonstrate sex-specific dysfunction of developing cortical circuits with loss of function of a high-confidence ASD-risk gene. Importantly, we demonstrate a distinct, female-specific dysfunction of mGluR5- ERα signaling pathways that drive excitability. For the Phase 2 extension of this work, we propose to determine the female-specific, Pten-regulated cellular and molecular alterations in cortical neurons that give rise to hyperexcitability of circuits. In Aim 1, we will determine the sex-specific, mGluR5 and ERα -regulated neuronal and synaptic properties in L5 PTEN KO neurons. In Aim 2 we will determine the sex- specific, PTEN-regulated ribosome- associated transcripts in L5 cortical neurons and their regulation by mGluR5 and ERα. Our results reveal sex-specific and estrus cycle-dependent deficits in sensory-processing in Pten loss of function models. In Aim 3 we will determine if a reduction in mGluR5 or ERα function corrects these sensory processing deficits and in Aim 4, we will examine the role of estrogen and estrus cycle in dysfunction of developing and mature cortical circuits and in vivo resting and sensory-driven EEG phenotypes in Pten loss of function models. Results of these aims are expected to provide knowledge of the sex-specific mechanisms by which ASD-risk genes regulate the development and function of sensory cortical circuits and affect sensory processing.


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 = $526,984 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/6/2026	NON-COMPETING CONTINUATION	$526,984
														Subtotal = $526,984

Issue Date FY: 2025 ( Subtotal = $526,984 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/13/2025	NON-COMPETING CONTINUATION	$526,984
2025	2020	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/4/2025	NEW	$0
														Subtotal = $526,984

Issue Date FY: 2024 ( Subtotal = $511,174 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/1/2024	EXTENSION WITH OR WITHOUT FUNDS	$511,174
														Subtotal = $511,174

Issue Date FY: 2020 ( Subtotal = $2,096,266 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/16/2020	NEW	$1,558,970
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/4/2020	NEW	$537,296
														Subtotal = $2,096,266

Grand Total All Awards = $3,661,408

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Sex-specific mechanisms of cortical circuit dysfunction in a mouse ASD model

Award Number: R37NS114516

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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