Abstract Synaptic activity results in long-lasting alterations of neuronal properties, which require gene expression regulation. PYK2 is a calcium-activated non-receptor protein tyrosine kinase highly expressed in hippocampal neurons and involved in synaptic functions. PYK2 also shuttles between the nucleus and the cytoplasm. We show that glutamate stimulation induces PYK2 accumulation in the nucleus of hippocampal neurons in culture through activation of NMDA receptors, L-type voltage-gated Ca 2+ channels, and calcineurin. NMDA receptor stimulation also increases nuclear location and interaction with PYK2 of methyl-CpG binding domain protein 2 (MBD2), a modulator of histone modifications and nucleosome remodeling. In PYK2-KO neurons, MBD2 nuclear translocation is diminished, acetylation of histone H4-Lys5 is decreased, and methylation of histone H3-Lys4 is increased. The transcriptome is modified in PYK2-KO hippocampus with a decreased expression of genes coding for excitatory synaptic proteins. In cultured neurons, the absence of PYK2 enhances the glutamate-induced downregulation of synaptic protein transcripts related to epilepsy pathophysiology. In wild-type mice, pilocarpine-induced status epilepticus increases PYK2 and MBD2 nuclear localization in hippocampal neurons, especially in CA3. In PYK2-KO mice, aberrant synaptic sprouting and cell death triggered by status epilepticus are reduced in CA3 compared to wild-type littermates. In PYK2-KO neurons in culture, glutamate-induced cell death is attenuated, and this effect is abolished by re-expression of wild-type PYK2 but not of mutated PYK2 unable to translocate to the nucleus. In summary, our study indicates that regulated PYK2 nuclear translocation in hippocampal neurons may facilitate transcription by removing MBD2 from the active chromatin and may contribute to seizure-induced neurotoxicity.
Giralt et al. (Wed,) studied this question.
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