CA3-Restricted BDNF Knockout as a Model of Abnormal Traits in Social Behaviors

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DESCRIPTION (provided by applicant): Antisocial personality disorder (ASPD) is "...a pervasive pattern of disregard for, and violation of, the rights of others that begins in childhood or early adolescence and continues into adulthood." ASPD is found in 1.0 % of the U.S. adult population. People with ASPD break social norms, lie repeatedly, place others at risk for their own benefit, and demonstrate a profound lack of remorse. What is referred to as psychopathy or sociopathy is a variant of ASPD characterized by instrumental/proactive aggression and lack of empathy; at the same time, there is no pathological anxiety, depression or cognitive deficits. While such behaviors impose severe burden on human society, ASPD is considered untreatable because of difficulty in clinical management of the patients and lack of intervention strategies. ASPD is predicted in youth with conduct disorder (CD); however, the fundamental mechanisms of CD/ASPD remain unknown and potential treatment strategies have not been investigated, partly because there is no good animal model. The goal of the proposal is to validate and investigate a novel empirical animal model of ASPD, mice with the deletion of BDNF gene in the hippocampal area CA3 (KO mice). These animals are aggressive and appear to have no empathy-like behaviors, but have normal cognition, anxiety and depression-like behaviors. This phenotype is reminiscent of ASPD symptoms in humans and was associated with reduced levels of serotonin and enhanced activity of serotonin receptor 3, whose activation inside hippocampus enhanced aggression. Surprisingly, this receptor attenuated hippocampal gamma oscillations. It is unclear through which neuronal mechanisms BDNF and serotonergic system in the hippocampus control aggression or empathy. The proposal represents a multidisciplinary study and combines behavioral and biochemical analyses, in vitro slice recording and pharmacogenetics to addresses the following questions: Which forms of empathy-like behaviors are compromised in KO mice? What changes in the hippocampus of KO mice may be relevant to the escalated aggression? Can pharmacological intervention with these changes attenuate escalated aggression and increase empathy-like behaviors? Such studies may validate BDNF CA3 KO mice as a model of ASPD and promote development of novel therapies for ASPD.