Biological roles of CLCN4 in human neuronal development

Abstract

CLCN4 encodes voltage-gated chloride channel 4 (CLC-4) that is highly expressed in the brain relative to the other tissues. Variants in CLCN4 are associated with epileptic seizures, intellectual disability and autistic traits, implying the functional significance of CLCN4 in brain development and diseases. However, little is known about the pathophysiological roles of CLCN4 in human brain development. To investigate the cellular and molecular function of CLCN4 in human neuronal development, we utilized neural progenitor cells (NPCs) derived from human pluripotent stem cells (PSCs) and manipulated expression level of CLCN4 in NPCs. In this presentation, the effects of CLCN4 depletion on the proliferation rate of NPCs, morphology and electrophysiological properties of differentiated neurons will be addressed. Furthermore, downstream targets of CLCN4 in neuronal development will be discussed. Lastly, the effects of antipsychotic medication on cellular and molecular phenotypes in CLCN4 depleted neurons will be discussed. Our work will expand our knowledge on the biological roles of CLCN4 in human neurogenesis and will provide insights on drug discovery for patients who express less CLCN4 in neurons.