Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington's Disease.

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 GABAA receptors (GABAARs). 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 GABAAR 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.