title: Genetic inhibition of CaMKII in dorsal striatal medium spiny neurons reduces functional excitatory synapses and enhances intrinsic excitability.
abstract: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is abundant in striatal medium spiny neurons (MSNs). CaMKII is dynamically regulated by changes in dopamine signaling, as occurs in Parkinson's disease as well as addiction. Although CaMKII has been extensively studied in the hippocampus where it regulates excitatory synaptic transmission, relatively little is known about how it modulates neuronal function in the striatum. Therefore, we examined the impact of selectively overexpressing an EGFP-fused CaMKII inhibitory peptide (EAC3I) in striatal medium spiny neurons (MSNs) using a novel transgenic mouse model. EAC3I-expressing cells exhibited markedly decreased excitatory transmission, indicated by a decrease in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs). This decrease was not accompanied by changes in the probability of release, levels of glutamate at the synapse, or changes in dendritic spine density. CaMKII regulation of the AMPA receptor subunit GluA1 is a major means by which the kinase regulates neuronal function in the hippocampus. We found that the decrease in striatal excitatory transmission seen in the EAC3I mice is mimicked by deletion of GluA1. Further, while CaMKII inhibition decreased excitatory transmission onto MSNs, it increased their intrinsic excitability. 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Klug
authors.forename: Brian N
authors.initials: BN
authors.lastname: Mathur
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Kash
authors.forename: Hui-Dong
authors.initials: HD
authors.lastname: Wang
authors.forename: Robert T
authors.initials: RT
authors.lastname: Matthews
authors.forename: A J
authors.initials: AJ
authors.lastname: Robison
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Ariel Y
authors.initials: AY
authors.lastname: Deutch
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010455:Peptides; D018091:Receptors, AMPA