On January 17th, the Journal of Neuroscience published a report from ION entitled “Differential roles of NR2A- and NR2B-containing NMDA receptors in activity-dependent BDNF gene regulation and limbic epileptogenesis”. This work was done by graduate student Qian Chen and fellow students from the Lab of Neurobiology of Disease, under the supervision of Dr. Zhi-qi Xiong.

Epilepsy, which affects approximately nine million Chinese of all ages, may develop after common brain insults including stroke, trauma, febrile seizures, meningitis and encephalitis. The molecules that link brain injuries to epileptogenesis are unknown. Fleeting activation of NMDA receptors 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. Qian Chen and colleagues showed that NR2A-containing NMDA receptors play critical roles in activity-dependent BDNF gene regulation and limbic epileptogenesis. They 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, while 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 on 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.