利鲁唑恢复等位基因特异性表达介导的LINC02449–CPLX1失调引起的回路和行为功能异常

Abstract

Background and HypothesisAllele-specific expression (ASE) of long non-coding RNAs (lncRNAs) links genetic variation to synaptic dysfunction in psychiatric disorders. We previously identified a disease-associated ASE shift in LINC02449 at rs149707223 (C/G), with preferential expression of the alternative G allele in bipolar disorder (BD) and schizophrenia (SZ). Overexpression of LINC02449-G induced social deficits, repetitive behaviors, and enhanced excitatory synaptic transmission in the medial prefrontal cortex-nucleus accumbens (mPFC-NAc) circuit via upregulation of CPLX1. We hypothesized that these abnormalities are mediated by glutamatergic hyperexcitability and are pharmacologically reversible.Study DesignAdult C57BL/6 mice received mPFC-targeted AAV-mediated LINC02449-G overexpression followed by systemic administration of Riluzole. Molecular, behavioral, and electrophysiological analyses were performed.Study ResultsRiluzole dose-dependently normalized elevated Cplx1 expression induced by LINC02449-G in mice. Behavioral assays showed significant rescue of social interaction deficits and reductions in excessive grooming and marble-burying behavior. Whole-cell recordings revealed that Riluzole restored increased mEPSC frequency and amplitude in NAc neurons to control levels, indicating correction of mPFC-NAc circuit hyperexcitability.ConclusionsThese results demonstrate that synaptic and behavioral abnormalities caused by ASE-driven lncRNA dysregulation are pharmacologically reversible. Riluzole represents a promising candidate for repurposing in neuropsychiatric disorders characterized by glutamatergic imbalance and frontostriatal circuit dysfunction, and highlights ASE-regulated lncRNAs as actionable therapeutic targets.