# Identifying Convergent Circuit Disruptions Across Genetically-Distinct Models of Autism

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $408,494

## Abstract

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.

## Key facts

- **NIH application ID:** 10933395
- **Project number:** 5R01HD111753-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Benjamin D Auerbach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $408,494
- **Award type:** 5
- **Project period:** 2023-09-22 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933395

## Citation

> US National Institutes of Health, RePORTER application 10933395, Identifying Convergent Circuit Disruptions Across Genetically-Distinct Models of Autism (5R01HD111753-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10933395. Licensed CC0.

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