title: Overexpression of αCaMKII impairs behavioral flexibility and NMDAR-dependent long-term depression in the medial prefrontal cortex.
abstract: The medial prefrontal cortex (mPFC) participates in the behavioral flexibility. As a major downstream molecule in the NMDA receptor signaling, alpha-Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) is crucial for hippocampal long-term potentiation (LTP) and hippocampus-related memory. However, the role of αCaMKII in mPFC-related behavioral flexibility and mPFC synaptic plasticity remains elusive. In the present study, using chemical-genetic approaches to temporally up-regulate αCaMKII activity, we found that αCaMKII-F89G transgenic mice exhibited impaired behavioral flexibility in Y-water maze arm reversal task. Notably, in vitro electrophysiological analysis showed normal basal synaptic transmission, LTP and depotentiation, but selectively impaired NMDAR-dependent long-term depression (LTD) in the mPFC of αCaMKII-F89G transgenic mice. In accordance with the deficit in NMDAR-dependent LTD, αCaMKII-F89G transgenic mice exhibited impaired AMPAR internalization during NMDAR-dependent chemical LTD expression in the mPFC. Furthermore, the above deficits in behavioral flexibility, NMDAR-dependent LTD and AMPAR internalization could all be reversed by 1-naphthylmethyl (NM)-PP1, a specific inhibitor of exogenous αCaMKII-F89G activity. Taken together, our results for the first time indicate that αCaMKII overexpression in the forebrain impairs behavioral flexibility and NMDAR-dependent LTD in the mPFC, and supports the notion that there is a close relationship between NMDAR-dependent LTD and behavioral flexibility.
authors.affiliation: Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.affiliation: Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: xhcao@brain.ecnu.edu.cn.
authors.forename: X
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials; D036881:Long-Term Synaptic Depression; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012193:Reversal Learning / Q000502:physiology*
chemical_list: D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: AMPAR internalization; behavioral flexibility; long-term depression; medial prefrontal cortex; αCaMKII