Figure 6. Schematic representation of postulated disease mechanisms in KCC2-EIMFS.

A post-synaptic neuron is schematically represented for (a) wild-type and (b) mutant KCC2 in EIMFS. Neurotransmitters and ions are depicted as shapes, namely GABA (red circle), potassium (K⁺, magenta diamond) and chloride (Cl⁻, blue circle). The mature KCC2 transporter (orange) with N-linked glycosylated extracellular domains (black branched structure) is located at the synaptic membrane. The GABA_A receptor (GABA_AR) is a purple oval. In normal mature neuronal cells (a) KCC2 transporter (bold orange) maintains low intraneuronal chloride (represented by blue fluid level) through chloride extrusion (solid orange lines). With GABA binding, the resultant gradient allows an influx of chloride via the GABA_AR resulting in a hyperpolarizing IPSP (inhibitory post-synaptic potential), which contributes to neuronal inhibition. In KCC2-EIMFS (b) a number of mechanisms contribute to loss of KCC2 function (faded orange KCC2 transporter) and impaired transporter ability to extrude chloride (dashed orange lines), including reduced cell surface transporter expression and abnormal protein glycosylation. This results in a depolarizing inhibitory postsynaptic potential, thereby leading to impaired neuronal inhibition.