Genetic Inhibition of CaMKII in Dorsal Striatal Medium Spiny Neurons Reduces Functional Excitatory Synapses and Enhances Intrinsic Excitability

Jason R. Klug, Brian N. Mathur, Thomas L. Kash, Hui Dong Wang, Robert T. Matthews, A. J. Robison, Mark E. Anderson, Ariel Y. Deutch, David M. Lovinger, Roger J. Colbran, Danny G. Winder

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Abstract

Ca2+/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.

Original languageEnglish (US)
Article numbere45323
JournalPloS one
Volume7
Issue number9
DOIs
StatePublished - Sep 21 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Klug, J. R., Mathur, B. N., Kash, T. L., Wang, H. D., Matthews, R. T., Robison, A. J., Anderson, M. E., Deutch, A. Y., Lovinger, D. M., Colbran, R. J., & Winder, D. G. (2012). Genetic Inhibition of CaMKII in Dorsal Striatal Medium Spiny Neurons Reduces Functional Excitatory Synapses and Enhances Intrinsic Excitability. PloS one, 7(9), [e45323]. https://doi.org/10.1371/journal.pone.0045323