Role of CaMKII and the GluN2B subunit of the NMDAR in dorsal striatal glutamatergic synaptic transmission, MSN morphology and striatal-based behaviors

Abstract

The role of striatal Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the GluN2B subunit of the NMDA receptor in excitatory glutamatergic transmission, morphology and behavior are presented in this thesis. The first half of this thesis examines a transgenic mouse which expresses a CaMKII inhibitory peptide (EAC3I) in dorsal striatal medium spiny neurons (MSNs). We find that MSN CaMKII inhibition is associated with a reduction in functional synapse number, increased excitability, decreased dendritic length/complexity and disrupted operant responding on a random ratio schedule. These data suggest that CaMKII plays a critical role in setting the excitability rheostat of striatal MSNs by coordinating excitatory synaptic drive and the resulting depolarization response as well as contributing to goal-directed behaviors.

The second half of this thesis explores the loss of the striatal GluN2B subunit of the NMDA receptor. We utilize a conditional GluN2B KO mouse to study alterations in basal synaptic transmission, morphology and behavior. We find that early postnatal deletion of GluN2B leads to an increase in postsynaptic AMPAR-mediated synaptic transmission and a decrease in dendritic spine density, which may be due to the loss of silent synapses or synapses lacking AMPARs. Behaviorally, the loss of GluN2B leads to enhanced locomotor activity in a novel open field and disruptions in performance on of rotarod. Delayed deletion of GluN2B (P45) yields a similar basal synaptic transmission phenotype as seen with early deletion, but with a decrease in quantal content. Behaviorally, delayed deletion of GluN2B rescues locomotor activity, but results in greater deficits in simple motor learning. These studies show the importance of the GluN2B subunit in excitatory synaptic transmission, dendritic spine density, and behavior.