Description:
<jats:p>Intracellular chloride (Cl<jats:sup>–</jats:sup>) 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<jats:sup>–</jats:sup> permeable GABA<jats:sub>A</jats:sub> receptors (GABA<jats:sub>A</jats:sub>Rs). The intracellular Cl<jats:sup>–</jats:sup> concentration is primarily maintained by the antagonistic actions of two cation-chloride cotransporters (CCCs): Cl<jats:sup>–</jats:sup>-importing Na<jats:sup>+</jats:sup>-K<jats:sup>+</jats:sup>-Cl<jats:sup>–</jats:sup> co-transporter-1 (NKCC1) and Cl<jats:sup>–</jats:sup> -exporting K<jats:sup>+</jats:sup>-Cl<jats:sup>–</jats:sup> co-transporter-2 (KCC2). In mature neurons in the healthy brain, KCC2 expression is higher than NKCC1, leading to lower levels of intracellular Cl<jats:sup>–</jats:sup>, and Cl<jats:sup>–</jats:sup> influx upon GABA<jats:sub>A</jats:sub>R 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<jats:sup>–</jats:sup> accumulation and GABA-mediated excitation. In Huntington’s disease (HD), KCC2- and NKCC1-mediated Cl<jats:sup>–</jats:sup>-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<jats:sup>–</jats:sup> (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.</jats:p>