Figure 1.

Potential mechanism of activity-dependent transcriptional repression by MeCP2. Neuronal activity (induced in cultured neurons by KCl, kainic acid or bicuculline treatment) leads to membrane depolarization, causing Ca²⁺ to enter through synaptic NMDA receptors (NMDA-R) or membrane voltage-gated Ca²⁺ channels (VGCC). This Ca²⁺ influx triggers a signaling pathway (mechanism not elucidated) to phosphorylate MeCP2 at residue Threonine (T) 308. Phosphorylation at T308 blocks the interaction of MeCP2 with the NCoR/SMRT co-repressor complex, which is responsible for transcriptional repression in wild-type (WT) neurons. Lack of phosphorylation at this residue due to missense point mutations may contribute to Rett syndrome (RTT): some of the genes that are regulated via this mechanism include Npas4 and Bdnf, which are required for development of inhibitory synapses onto excitatory neurons, E/I balance, and activity-dependent plasticity of circuits. Inset (left, bottom): Bridge on the river Khwae Yai in Thailand, as depicted in the 1957 Academy Award-winning film 'The Bridge on the River Kwai'. The central bridge spans bear a striking resemblance to the structure of DNA, and remind us that MeCP2 can act as an activity-dependent 'bridge' between NCoR and chromatin.