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.