title: Effects of prefrontal cortex and hippocampal NMDA NR1-subunit deletion on complex cognitive and social behaviors.
abstract: Glutamate N-methyl-D-aspartate receptors (NMDARs) in the medial prefrontal cortex (mPFC) and hippocampus may play an integral role in complex cognitive and social deficits associated with a number of psychiatric illnesses including autism, mood disorders, and schizophrenia. We used localized infusions of adeno-associated virus Cre-recombinase in adult, targeted knock-in mice with loxP sites flanking exons 11-22 of the NR1 gene to investigate the effects of chronic NMDAR dysfunction in the mPFC and CA3 hippocampus on cognitive and social behavior. A 5-choice serial reaction time task (5-CSRTT) was used to monitor aspects of cognitive function that included attention and response inhibition. Social behavior was assessed using Crowley׳s sociability and preference for social novelty protocol. Chronic NMDAR dysfunction localized to the anterior cingulate/prelimbic mPFC or dorsal CA3 hippocampus differentially affected the response inhibition and social interaction. mPFC NR1-deletion increased perseverative responding in the 5-CSRTT and enhanced preference for social novelty, whereas CA3 NR1-deletion increased premature responding in the 5-CSRTT and decreased social approach behavior. These findings suggest that mPFC and CA3 NMDARs play selective roles in regulating compulsive and impulsive behavior, respectively. Furthermore, these findings are consistent with emerging evidence that these behaviors are mediated by distinct, albeit overlapping, neural circuits. Our data also suggest that NMDARs in these regions uniquely contribute to the expression of normal social behavior. In this case, mPFC and CA3 NMDARs appear to inhibit and facilitate aspects of social interaction, respectively. The latter dissociation raises the possibility that distinct circuits contribute to the expression of social intrusiveness and impoverished social interaction.
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA. Electronic address: janet.finlay@wwu.edu.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Finlay
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
authors.forename: Ginger A
authors.initials: GA
authors.lastname: Dunham
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
authors.forename: Analiesse M
authors.initials: AM
authors.lastname: Isherwood
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
authors.forename: Chelsea J
authors.initials: CJ
authors.lastname: Newton
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
authors.forename: Thuyanh V
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Reppar
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Snitkovski
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Paschall
authors.affiliation: Department of Psychiatry, Dallas Veterans Administration Medical Center, University of Texas Southwestern, Dallas, TX, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Greene
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology*; D017353:Gene Deletion; D006624:Hippocampus / Q000502:physiology*; D007175:Impulsive Behavior / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000502:physiology*; D011930:Reaction Time; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D012919:Social Behavior
chemical_list: C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Attention; Hippocampus; NMDA receptor; Prefrontal cortex; Response inhibition; Social interaction