Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in...

Intracellular chloride (Cl^-) levels in mature neurons must be tightly regulated for the maintenance of fast synaptic inhibition. In the mature central nervous system (CNS), synaptic inhibition is primarily mediated by gamma-amino butyric acid (GABA), which binds to Cl^- permeable GABA_A receptors (GABA_ARs). The intracellular Cl^- concentration is primarily maintained by the antagonistic actions of two cation-chloride cotransporters (CCCs): Cl^--importing Na⁺-K⁺-Cl^- co-transporter-1 (NKCC1) and Cl^- -exporting K⁺-Cl^- co-transporter-2 (KCC2). In mature neurons in the healthy brain, KCC2 expression is higher than NKCC1, leading to lower levels of intracellular Cl^-, and Cl^- influx upon GABA_AR activation. However, in neurons of the immature brain or in neurological disorders such as epilepsy and traumatic brain injury, impaired KCC2 function and/or enhanced NKCC1 expression lead to intracellular Cl^- accumulation and GABA-mediated excitation. In Huntington's disease (HD), KCC2- and NKCC1-mediated Cl^--regulation are also altered, which leads to GABA-mediated excitation and contributes to the development of cognitive and motor impairments. This review summarizes the role of Cl^- (dys)regulation in the healthy and HD brain, with a focus on the basal ganglia (BG) circuitry and CCCs as potential therapeutic targets in the treatment of HD.