NMDA receptor blockade in the hippocampus improves the post-weaning social isolation-induced emotional dysfunctions

Abstract

Accumulating epidemiological evidence shows that early life events have long-term effects on the susceptibility to subsequent stress exposure during adulthood Here we reported the effects of post-weaning social isolation an animal model of early life adversities on the behavioral responses to acute stress in adult mice At postnatal day 21 mice were randomly assigned to group housing (GH) or individual cages for 8 weeks and behavioral tests were performed at the age of 3 months Socially isolated (SI) mice exhibited higher spontaneous locomotor activity depression-like behavior impaired sensorimotor gating and more aggressive behavior but not attack number Moreover acute stress significantly exacerbated attack counts of SI mice to the intruder BABL/c mice and induced higher levels of anxiety-like behavior in the SI mice than in GH mice In addition post-weaning social isolation increased hippocampal surface expression of NR2A and NR2B subunits Bilateral hippocampal infusion of the NMDA antagonist MK-801or ifenprodil reversed stress-induced attack behavior in the SI mice Moreover the specific knockdown of NR2B expression in the hippocampus by shRNA transfection technique significantly reduced the stress-induced attack level of SI mice Thus the increased levels of NMDA-Rs in the hippocampus may be responsible for the post-weaning social isolation-induced emotional alterations Additionally SI mice exhibited an increased level of eEF2 phosphorylation in the hippocampus and acute stress induced even higher levels of eEF2 phosphorylation This corresponds to the stress-induced outburst of attack behavior in SI mice Furthermore NMDA-R blockade increased the eEF2 activity and induction of BDNF expression in the hippocampus Microinjection of eEF2 kinase (eEF2K) inhibitors into ventral hippocampus mimicked MK-801-induced anti-aggressive response and increased BDNF expression Knockdown of BDNF expression in the hippocampus blocked the behavioral effects of MK-801 and eEF2K inhibitor Thus anti-aggressive effects of MK-801 are mediated through the increased eEF2 activity leading to induction of BDNF expression Conclusion: These results suggested the isolation-induced increased levels of NMDA receptors in the hippocampus may mediate the stress-induced aggression NMDA-R blockade reduces the attack and depression-like behavior which requires the activation of eEF2-BDNF pathway Our findings could yield novel therapeutic targets for aggression

Date of Award	2015 Jan 21
Original language	English
Supervisor	Po-Wu Gean (Supervisor)