Neuronal chloride and excitability - the big impact of small changes

•Small changes in the neuronal Cl− gradient significantly impact excitability.•Relatively minor perturbations in Cl− homeostasis degrade neuronal coding.•Cl− gradients bidirectionally regulate glutamatergic synaptic plasticity.•Dysregulated Cl− gradients contribute to excitability disorders such as epilepsy.•Overwhelmed Cl− extrusion mechanisms contribute to seizure propagation.

Synaptic inhibition is a critical regulator of neuronal excitability, and in the mature brain the majority of synaptic inhibition is mediated by Cl−-permeable GABAA receptors. Unlike other physiologically relevant ions, Cl− is dynamically regulated, and alterations in the Cl− gradient can have significant impact on neuronal excitability. Due to changes in the neuronal Cl− concentration, GABAergic transmission can bidirectionally regulate the induction of excitatory synaptic plasticity and gate the closing of the critical period for monocular deprivation in visual cortex. GABAergic circuitry can also provide a powerful restraining mechanism for the spread of excitation, however Cl− extrusion mechanisms can become overwhelmed and GABA can paradoxically contribute to pathological excitation such as the propagation of seizure activity.