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

NEUROBIOLOGY OF DISEASE

卷:116

Article

Rosenberg, Evan C.^2,3  Lippman-Bell, Jocelyn J.^1,2,4  Handy, Marcus¹  Soldan, Samantha S.¹  Rakhade, Sanjay²  Hilario-Gomez, Cristina²  Folweiler, Kaitlyn¹  Jacobs, Leah¹  Jensen, Frances E.^1,2 

[1] Univ Penn, Dept Neurol, Perelman Sch Med, 3400 Spruce St, Philadelphia, PA 19104 USA

[2] Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA

[3] NYU, Langone Med Ctr, New York, NY 10016 USA

[4] Philadelphia Coll Osteopath Med, Dept Biomed Sci, Philadelphia, PA 19131 USA

关键词: MeCP2;    Seizure;    Rett Syndrome;    Autism spectrum disorder;    AMPARs;    LT-VGCCs;   

DOI  :  10.1016/j.nbd.2018.05.001

来源: Elsevier

【 摘 要 】

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 Ca(v)1.2 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, 5421, 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.

【 授权许可】

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