Figure 1. NMDARs in epilepsy. Reports by three independent groups suggest mutations in NMDA receptor NR2A subtype (GRIN2A; NR2A) underlie a subset of epilepsy-aphasia spectrum disorders.

The groups found de novo mutations in NR2A in 9%-20% of patients displaying a range of epileptic disorders characterized by abnormal slow wave activity, seizure and language deficits. Studies in cell culture suggest the disease-associated mutations lead to abnormal NMDAR kinetics.

In early childhood, NMDARs are heterotetrameric ion channels (I[a]) consisting of two subunits of NMDA receptor NR1 subtype (GRIN1; NR1) and two subunits of NR2A. Normally, binding of the excitatory neurotransmitter glutamate leads to opening of the channel, allowing influx of ions into neurons (I[b]). After a short time, the channel closes, leading to moderate accumulation of ions in the cytoplasm and normal neurological activity (I[c]).

In some patients with epilepsy-aphasia spectrum disorders, mutations in NR2A (II[a]) compromise the kinetics of NMDAR activity. Glutamate binding to mutant NR2A-containing NMDARs (II[b]) leads to a prolonged open state (II[c]) and excessive ion influx, which in turn causes overactivation of downstream intracellular signaling, speech disorders and seizures.