OVEREXPRESSION OF αCaMKII IMPAIRS BEHAVIORAL FLEXIBILITY AND NMDAR-DEPENDENT LONG-TERM DEPRESSION IN THE MEDIAL PREFRONTAL CORTEX

The medial prefrontal cortex (mPFC) participates in the behavioral flexibility. As a major downstream molecule in the NMDA receptor signaling, alpha-Ca2+/calmodulin-dependent protein kinase II (aCaMKII) is crucial for hippocampal long-term potentiation (LTP) and hippocampus-related memory. However, the role of aCaMKII in mPFC-related behavioral flexibility and mPFC synaptic plasticity remains elusive. In the present study, using chemical-genetic approaches to temporally up-regulate aCaMKII activity, we found that aCaMKII-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 aCaMKII-F89G transgenic mice. In accordance with the deficit in NMDAR-dependent LTD, aCaMKII-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 aCaMKII-F89G activity. Taken together, our results for the first time indicate that aCaMKII 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. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.