1.Differential Roles Of NR2A And NR2B-Containing NMDA Receptors In Activity-Dependent BDNF Gene Regulation And Limbic 2.CDKL5/STK9 RNA Interference Blocks Neural Radial Migration

Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and ERK1/2 activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, while inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury. Mutations in the CDKL5 gene (Cyclin Dependent Kinase-Like 5, also named as STK9, Serine Threonine Kinase 9) are associated with early-onset mental retardation and severe neurological symptoms. The clinical features meet the criteria for the early-onset of Rett syndrome, and suggest that CDKL5/STK9 plays important roles in brain development. Here we show that CDKL5/STK9 regulates neuronal migration. CDKL5/STK9 mRNA and protein were highly expressed in the developing rat brain and decreased rapidly in the adulthood. In vivo reduced amounts of STK9 caused inhibition of cortical neuronal migration. Our findings suggest that STK9 plays a critical role in neuronal migration during corticogenesis. Our studies together with the clinical findings shed light on the critical roles of STK9 in the atypical Rett syndrome.