primary roles within neurons: Establishing the chloride ion gradient necessary for postsynaptic inhibition Protecting neuronal networks against stimulation-induced excitotoxicity Contributing to dendritic spine morphogenesis and glutamatergic synaptic function Postsynaptic inhibition KCC2 is a potassium (K+)/chloride (Cl−) symporter that maintains chloride homeostasis in neurons. The electrochemical chloride gradient established by KCC2 activity is crucial for classical postsynaptic inhibition through GABAA receptors and glycine receptors in the central nervous system. KCC2 utilizes the potassium gradient generated by the Na+/K+ pump to drive chloride extrusion from neurons. In fact, any disruption of the neuronal K+ gradient would indirectly affect KCC2 activity. Loss of KCC2 following neuronal damage (i.e. ischemia, spinal cord damage, physical trauma to the central nervous system) results in the loss of inhibitory regulation and the subsequent development of neuronal hyperexcitability, motor spasticity, and seizure-like activity as GABAA receptors and glycine receptors revert from hyperpolarizing to depolarizing postsynaptic effects. Cellular protection High levels of stimulation and subsequent ionic influx through activated ion channels can result in cellular swelling as osmotically-obliged water is drawn into neurons along with ionic solutes. This phenomenon is known as excitotoxicity. KCC2 has been shown to be activated by cell-swelling, and may therefore play a role in eliminating excess ions following periods of high stimulation in order to maintain steady-state neuronal volume and prevent cells from bursting. This role may also account for the fact that KCC2 has been known to colocalize near excitatory synapses, even though its primary role is to establish the chloride gradient for postsynaptic inhibition. Morphogenesis and function of glutamatergic synapses In addition to controlling the efficacy of GABAergic synapses through chloride homeostasis, KCC2 play a critical role in the morphogenesis and function of glutamatergic synapses within the central nervous system. Studies on hippocampal tissue in KCC2 knockout animals showed that neurons lacking KCC2 have stunted dendritic growth and malformed dendritic spines. Recent studies demonstrate that KCC2 plays a critical role in the structure and function of dendritic spines which host most excitatory synapses in cortical neurons. Through an interaction with actin cytoskeleton, KCC2 forms a molecular barrier to the diffusion of transmembrane proteins within dendritic spines, thereby regulating the local confinement of AMPA receptors and synaptic potency. It has been proposed that the downregulation of KCC2 observed following neuronal trauma, and the consequent depolarizing shift of GABAA-mediated synapses, may be an aspect of neuronal de-differentiation. De-differentiation of damaged portions of the nervous