Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders

Abstract

Neurological diseases including Alzheimer's, Huntington's disease, Parkinson's disease, Down syndrome and epilepsy, and neuropsychiatric disorders such as schizophrenia, are conditions that affect not only individuals but societies on a global scale. Current therapies offer a means for small symptomatic relief, but recently there has been increasing demand for therapeutic alternatives. The γ-aminobutyric acid (GABA)ergic signaling system has been investigated for developing new therapies as it has been noted that any dysfunction or changes to this system can contribute to disease progression. Expression of the K-Cl-2 (KCC2) and N-K-C1-1 (NKCC1) cation-chloride cotransporters (CCCs) has recently been linked to the disruption of GABAergic activity by affecting the polarity of GABA_A receptor signaling. KCC2 and NKCC1 play a part in multiple neurological and neuropsychiatric disorders, making them a target of interest for potential therapies. This review explores current research suggesting the pathophysiological role and therapeutic importance of KCC2 and NKCC1 in neuropsychiatric and neurological disorders.

Keywords: Alzheimer’s disease; Down syndrome; GABA; Huntington’s disease; KCC2; NKCC1; Parkinson’s disease; epilepsy; neurodevelopment; neuropsychiatric; schizophrenia.

Figure 1

Dysregulation of chloride homeostasis leads to excitatory/inhibitory (E/I) imbalance. An altered expression of KCC2 and NKCC1 in neurological diseases including Alzheimer’s, Huntington’s, and Parkinson’s disease, schizophrenia, Down syndrome and epilepsy could disrupt GABAergic transmission and promote an E/I imbalance. GABA_A receptor (GABA_AR) activation can shift the response from hyperpolarizing to depolarizing, contributing to enhanced network excitability. This process can be returned to normal by blocking NKCC1 with bumetanide.