Impaired cortical inhibitory neurons (IN) occur in many difficult-to-treat epilepsies and may be due to disruptions in early development. INs expressing somatostatin (SST) or parvalbumin (PV) are crucial to control excitation in the cortex. Our previous data shows that in mice PV-INs are activated one week after birth by the neurotransmitter glutamate acting on receptors containing either the GluN2C or GluN2D protein. When we block GluN2C/D pharmacologically at the end of the first week of life, PV-INs are defective at adult age. We suggest that glutamate activating INs early in life is an important developmental signal. Indeed, it was recently shown in humans that mutations of GluN2D result in severe drugresistant seizures in children. I hypothesize that disturbing early-life GluN2D activation leads to severe epilepsy, because SST- and PV-INs do not develop properly. To test this hypothesis, I will use electrophysiology, pharmacology, and genetics to see if activation of GluN2D is needed for INs to develop properly. I will also assess how excitatory onto SST- and PV-IN and IN inhibitory output develops after birth. Importantly, I will directly test if disrupting GluN2D activation causes epilepsy. After this study, we will understand how GluN2D activation affects IN maturation and how disruptions at early-age lead to epilepsy.
