Migraine mutations affecting the central glutamate synapse. Increased Ca2+ influx caused by familial hemiplegic migraine subtype 1 (FHM1) associated mutations in Cav2.1 channels enhance glutamate release from presynaptic terminals. Loss of Na+/K+ ATPase function, as seen in FHM2, indirectly reduces astrocyte uptake of glutamate, resulting in increased levels of the neurotransmitter in the synaptic cleft. FHM3 associated mutations can reduce firing of inhibitory interneurons or potentiate presynaptic action potential generation. Mutations in SLC4A4 inhibit glia-mediated acid secretion and thus free N-methyl-D-aspartate (NMDA) receptors from proton-mediated inhibition. Activity of EAAT1, the major glutamate transporter in the brain, is directly affected by a mutation in its sequence and indirectly by upregulation of MTDH, a likely consequence of a reported mutation in rs1835740. LRP1 has a role in glutamate signalling and has been shown to directly modulate NMDA-dependent calcium currents in vitro.