Caveolin‐1 regulation of DISC1 as a potential therapeutic target for schizophrenia

Abstract

BackgroundSchizophrenia (SZ) is a debilitating neuropsychiatric disorder manifested in early adulthood. Disrupted‐In‐Schizophrenia‐1 (DISC1) is a promising candidate gene for SZ, but the molecular mechanisms underlying its role in the pathogenesis of the disease is still poorly understood. Caveolin‐1 (Cav‐1) is a cholesterol‐binding and plasma membrane scaffolding protein implicated in neuronal signal transduction and plasticity. Here we examined the role of CAV1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo.Methods and resultsOverexpressing Cav‐1 in primary neonatal rodent neurons using a neuron specific synapsin promoter (SynCav1) isolated from hippocampi resulted in increased DISC1 and synaptic plasticity markers (PSD95, synaptobrevin, synaptophysin, and syntaxin‐1A). Similarly, SynCav1‐transfected differentiated human neurons derived from induced pluripotent stem cells (iPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Furthermore, these markers and DISC1 were significantly reduced in the hippocampi from Cav‐1 knockout (KO) mice. Finally, SynCav1 delivery to the hippocampus of Cav‐1 KO mice and neurons lacking Cav‐1 restored DISC1 protein expression as well as markers of synaptic plasticity.ConclusionThese findings show an important role for neuronal Cav‐1 as a mediator of DISC1; therefore, SynCav1 might be a potential therapeutic target for SZ.Support or Funding Information5 T32 MH 19934‐20