PT - JOURNAL ARTICLE AU - Ariadna Amador AU - Christopher D. Bostick AU - Heather Olson AU - Jurrian Peters AU - Chad R. Camp AU - Daniel Krizay AU - Wenjuan Chen AU - Wei Han AU - Weiting Tang AU - Ayla Kanber AU - Sukhan Kim AU - Jia Jie Teoh AU - Sabrina Petri AU - Hunki Paek AU - Ana Kim AU - Cathleen M. Lutz AU - Mu Yang AU - Scott J. Myers AU - Subhrajit Bhattacharya AU - Hongjie Yuan AU - David B. Goldstein AU - Annapurna Poduri AU - Michael J. Boland AU - Stephen F. Traynelis AU - Wayne N. Frankel TI - Modeling and treating <em>GRIN2A</em> developmental and epileptic encephalopathy in mice AID - 10.1101/737239 DP - 2019 Jan 01 TA - bioRxiv PG - 737239 4099 - http://biorxiv.org/content/early/2019/08/16/737239.short 4100 - http://biorxiv.org/content/early/2019/08/16/737239.full AB - NMDA receptors (NMDAR) play crucial roles in excitatory synaptic transmission. Rare variants of GRIN2A, which encodes the GluN2A NMDAR subunit, are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). A de novo missense variant, p.Ser644Gly (c.1930A&gt;G), was identified in a child with DEE, and Grin2a knockin mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibit altered hippocampal morphology at two weeks of age, and homozygotes exhibit lethal tonic-clonic seizures in the third week. Heterozygous adult mice display a variety of distinct features, including resistance to electrically induced partial seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with these observations, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of modeling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their extended utility in identifying and evaluating new therapies.