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Fluconazole reverses SHANK3-related autism-like deficits via lipid raft-driven IGF1R activation and prefrontal circuit remodeling

ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects approximately 61.8 million people globally1. Mutations in the postsynaptic scaffolding protein SHANK3 define a high-penetrance ASD subgroup characterized by excitatory synaptic dysfunction2,3, yet disease-modifying therapies are lacking. Although transient IGF1 application ameliorates synaptic defects in Shank3-deficient models4, strategies for sustained activation of IGF1 receptor (IGF1R) signaling remain elusive. Here, we repositioned the FDA-approved antifungal agent fluconazole5 as an effective therapy for SHANK3-related ASD. In Shank3-deficient mice, fluconazole restored social deficits and repetitive behaviors through remodeling postsynaptic scaffold proteins. Mechanistically, fluconazole promoted lipid raft assembly to drive IGF1R homodimerization and activation, triggering ERK-mediated antioxidant responses to restore synaptic architecture, evidenced by Homer1/PSD95 re-colocalization. Integrated single-cell/nucleus RNA sequencing revealed fluconazole-induced prefrontal circuit remodeling, involving expansion of Homer1⁺ glutamatergic neurons and enhanced VIP⁺ GABAergic interneuron function. Fluconazole specifically potentiated communication from VIP⁺ interneurons to synapse-proficient glutamatergic neurons, leading to the restoration of postsynaptic ultrastructure in deep-layer prefrontal cortex. This reconfigured network induced by fluconazole supported a sustained recovery through a self-reinforcing IGF1-IGF1R-ERK signaling loop, with VIP⁺ interneurons serving as a potential IGF1 source. Collectively, our findings establish fluconazole as a clinically translatable therapy for SHANK3-related ASD via IGF1R-driven synaptic remodeling.

ORGANISM(S): Mus musculus

PROVIDER: GSE313444 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Shank3 is an abundant excitatory postsynaptic scaffolding proteins implicated in various neurodevelopmental and psychiatric disorders, including ASD, Phelan-McDermid syndrome, intellectual disability, and schizophrenia. Shank3-mutant mice with a homozygous deletion of exons 14-16 (Shank3-HM mice) show ASD-like behavioral deficits and altered synaptic and neuronal functions, but little is known about how different ages, brain regions, and gene dosages contribute to transcriptomic phenotypes in these mice. Here, we performed RNA-Seq-based transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank3 heterozygous- and homozygous-mutant mice. In addition, juvenile and adult Shank3 homozygous-mutant forebrain transcriptomes were compared. Juvenile and adult forebrain transcriptomes from Shank3 homozygous-mutant mice showed the patterns that are opposite and similar to those observed in ASD: reverse-ASD and ASD-like patterns, respectively. Here, the juvenile reverse-ASD pattern involved synaptic gene upregulations and ribosomal and mitochondrial downregulations, whereas the adult ASD-like pattern involved opposite changes. Gene set enrichment analyses (GSEA) of brain regional transcripts in adult Shank3-HT and Shank3-HM mice revealed that the cortical, hippocampal, and striatal transcripts show distinctly altered biological functions and ASD-related/risk gene expressions. The cortex and striatum display ASD-like patterns whereas the hippocampus displays reverse-ASD patterns. The cortical ASD-like pattern more strongly involves ASD-risk genes whereas the striatal ASD-like pattern more strongly involves astrocyte/microglia genes. Shank3-HT and Shank3-HM transcripts in a given brain region display largely similar patterns in biological functions and ASD-related/risk gene expressions, suggestive of small gene dosage effects. These results suggest that heterozygous and homozygous Shank3 deletions in mice lead to age, brain region, and gene dosage-differential transcriptomic changes.

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Fluconazole reverses SHANK3-related autism-like deficits via lipid raft-driven IGF1R activation and prefrontal circuit remodeling

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