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AMPA receptors (AMPARs) are involved in the synaptic transmission of neurotransmitters in the central nervous system and one subset of these AMPARs are calcium-permeable (CP-AMPARs) because they lack the GluR2 subunit. In infants experiencing hypoxic seizures, these CP-AMPARs are upregulated and simultaneously, MeCP2, a transcription factor linked to autism spectrum disorder (ASD) becomes phosphorylated. MeCP2 is involved with synapse and dendrite development and neuronal maturation and thus, disruptions in its expression can lead to ASDs or epilepsy.
AMPAR blockers have been considered as antiepileptogenetic drug candidates though they are not specific enough to target only CP-AMPARs.
Bottom: CP-AMPAR antagonists reduce MeCP2 phosphorylation. AMPARs and LT-VGCCs mediate hypoxic seizure (HS)-induced MeCP2 S421 phosphorylation in vivo in P10 rats. Increased MeCP2 S421 phosphorylation 3h. post-HS (HS+V: n=17 vs. C+V n=14, p=0.0003) can be attenuated by in vivo pre-treatment with the AMPAR antagonist NBQX (20mg/kg, i.p.) (HS+NBQX: n=9, vs. HS+V, p<0.0001), the CP-AMPAR blocker IEM-1460 (20mg/kg, i.p.) (HS+IEM-1460: n=9, vs. HS+V p=0.0099), or the LT-VGCC antagonist nimodipine (10mg/kg, i.p.) (HS+NIMO: n=9, vs. HS+V p=0.0051)