Regulation of seizure-induced MeCP2 Ser421 phosphorylation in the developing brain

• Published in: Neurobiology of disease 2018-08, Vol.116, p.120-130
• Main Authors: Rosenberg, Evan C., Lippman-Bell, Jocelyn J., Handy, Marcus, Soldan, Samantha S., Rakhade, Sanjay, Hilario-Gomez, Cristina, Folweiler, Kaitlyn, Jacobs, Leah, Jensen, Frances E.
• Format: Article
• Language: English
• Subjects: AMPARs; Animals; Autism spectrum disorder; Cells, Cultured; Cerebral Cortex - growth & development; Cerebral Cortex - metabolism; Hippocampus - growth & development; Hippocampus - metabolism; LT-VGCCs; Male; MeCP2; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Phosphorylation - physiology; Rats; Rett Syndrome; Seizure; Seizures - genetics; Seizures - metabolism; Serine - genetics; Serine - metabolism
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2018.05.001

Neonatal seizures disrupt normal synaptic maturation and often lead to later-life epilepsy and cognitive deficits. During early life, the brain exhibits heightened synaptic plasticity, in part due to a developmental overabundance of CaV1.2 L-type voltage gated calcium (Ca2+) channels (LT-VGCCs) and Ca2+-permeable AMPARs (CP-AMPARs) lacking GluA2 subunits. We hypothesized that early-life seizures overactivate these channels, in turn dysregulating Ca2+-dependent signaling pathways including that of methyl CPG binding protein 2 (MeCP2), a transcription factor implicated in the autism spectrum disorder (ASD) Rett Syndrome. Here, we show that in vivo hypoxia-induced seizures (HS) in postnatal day (P)10 rats acutely induced phosphorylation of the neuronal-specific target of activity-dependent MeCP2 phosphorylation, S421, as well as its upstream activator CaMKII T286. We next identified mechanisms by which activity-dependent Ca2+ influx induced MeCP2 phosphorylation using in vitro cortical and hippocampal neuronal cultures at embryonic day (E)18 + 10 days in vitro (DIV). In contrast to the prevalent role of NMDARs in the adult brain, we found that both CP-AMPARs and LT-VGCCs mediated MeCP2 S421 and CaMKII T286 phosphorylation induced by kainic acid (KA) or high potassium chloride (KCl) stimulation. Furthermore, in vivo post-seizure treatment with the broad-spectrum AMPAR antagonist NBQX, the CP-AMPAR blocker IEM-1460, or the LT-VGCC antagonist nimodipine blocked seizure-induced MeCP2 phosphorylation. Collectively, these results demonstrate that early-life seizures dysregulate critical activity-dependent developmental signaling pathways, in part via CP-AMPAR and LT-VGCC activation, providing novel age-specific therapeutic targets for convergent pathways underlying epilepsy and ASDs. [Display omitted] •Neonatal hypoxic seizures induce phosphorylation of MeCP2 S421, a key mediator of activity-dependent plasticity.•Seizures also activate CaMKII T286, an upstream regulator of MeCP2 activity.•Blockade of calcium-permeable AMPARs and LT-VGCCs, both in vitro and in vivo, reverses seizure-induced MeCP2 phosphorylation.