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Published on: August 18, 2008
Riluzole Restores Circuit and Behavioral Function Altered by Allele-Specific Expression-Mediated LINC02449-CPLX1
Chaoying Ni1,2, Jin-Ming Liu1,3, Tengfei Yang1,2
1Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Background And Hypothesis:
Allele-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 Design:
Adult 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 Results:
Riluzole 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.
Conclusions:
These 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.
