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Thalamocortical disruption as a convergence point for schizophrenia risks

Award Number: R01MH139498
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/03/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Thalamocortical disruption as a convergence point for schizophrenia risks - Abstract In schizophrenia (SCZ) and other psychiatric disorders, positive symptoms, such as auditory hallucinations, are not well understood. Therefore, treatment options are limited, and most treatments are associated with devastating side effects that result in low adherence to antipsychotic medication regimens and increased suffering of the patient and family. Our knowledge of the mechanisms underlying positive symptoms is limited, mostly because we lack reliable biological markers or events that can be modeled and studied. In this proposal, we will elucidate the cellular manifestations of positive symptoms in mouse models of 2 of the strongest genetic predictors of SCZ, 22q11.2 microdeletion syndrome (22q11DS) and 3q29 microdeletion syndrome (3q29DS). These rare copy number variations (CNVs) increase the risk of SCZ by ~30 fold and ~40 fold, respectively. Psychotic symptoms are clinically indistinguishable between patients with SCZ who have these microdeletions and those who do not, and these symptoms usually appear during late adolescence/early adulthood. Our previous work in 22q11DS mice identified disrupted synaptic transmission specifically in thalamocortical (TC) projections between the auditory thalamus and auditory cortex (ACx), the brain areas associated with auditory hallucinations in humans. Disruption of TC projections in 22q11DS mice occurs at 3.5 months, which corresponds to early adulthood in humans and the age of positive symptom onset, and this disruption is rescued by antipsychotics. The TC deficit is caused by an elevated level of dopamine receptor 2 (Drd2), a common target of antipsychotics, and leads to reduced glutamate release from thalamic afferents. TC disruption leads to disturbances in neuronal activity and appearances of abnormal neuronal ensembles (i.e., clusters of concurrently firing neurons) in the ACx during silence, as measured by mesoscopic 2-photon imaging in awake 22q11DS mice. Our preliminary data showed a similar TC disruption in the ACx of 3q29DS mice. Therefore, the overall goal of this proposal is to identify the mechanistic overlap between SCZ risks. We will test the following hypothesis: SCZ risks, such as 22q11DS, 3q29DS, and other SCZ-associated CNVs, independently disrupt auditory TC projections to cause abnormal neuronal activity in the ACx. In Aim 1, we propose to characterize the specificity and age dependency of TC disruption in 3q29DS mice and elucidate the underlying cellular and molecular mechanisms. To generalize these findings, we will also test TC transmission in other SCZ-associated CNVs. In Aim 2, we will characterize the abnormal neuronal activities in the ACx of 3q29DS mice to find similarities with 22q11DS mice. We will also chemogenetically restore TC function to normalize neuronal activity in the ACx of 3q29DS mice and 22q11DS mice. This work will identify the common mechanisms and manifestations of positive symptoms in mice harboring CNVs that confer the strongest risks of SCZ.


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 = $662,341 )
2026	2026	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Mental Health Research Grants	000	2	2/11/2026	NON-COMPETING CONTINUATION	$662,341
														Subtotal = $662,341

Issue Date FY: 2025 ( Subtotal = $735,932 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Mental Health Research Grants	000	1	4/3/2025	NEW	$735,932
														Subtotal = $735,932

Grand Total All Awards = $1,398,273

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Thalamocortical disruption as a convergence point for schizophrenia risks

Award Number: R01MH139498

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/03/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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