Effects of prefrontal cortex and hippocampal NMDA NR1-subunit deletion on complex cognitive and social behaviors.

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.

Extracellular dopamine and norepinephrine in the developing rat prefrontal cortex: transient effects of early partial loss of dopamine.

Early developmental abnormalities affecting mesocortical dopamine (DA) neurons may result in later functional deficits that play a role in the emergence of psychiatric illness in adolescence/early adulthood. Little is known about the functional maturation of these neurons under either normal or abnormal conditions. In the present study, 6-hydroxydopamine was infused into the rat medial prefrontal cortex (mPFC) on postnatal day (PN) 12-14. On PN30-35, 45-50, and 60-65, mPFC extracellular DA and norepinephrine (NE) concentrations were monitored in intact and lesioned rats using in vivo microdialysis. Extracellular DA and NE concentrations in the intact mPFC remain fairly stable across development; one exception being a trend for acute tailshock-evoked DA concentrations to increase as a function of age. Lesioned rats sustained a persistent (approximately 50%) decrease in mPFC tissue DA concentrations. Tailshock-evoked increases in mPFC extracellular DA were attenuated in lesioned rats tested on PN30-35, but not PN45-50 or 60-65. Basal and evoked extracellular NE was unaffected in lesioned rats tested at any age, despite a persistent (approximately 25%) decrease in tissue NE content. Horizontal locomotor activity was also assessed in the present study. Results of previous studies suggest this behavior is modulated by mesoprefrontal DA neurons. Although not significant, acute tailshock- and acute amphetamine-evoked horizontal locomotor activity tended to be attenuated in lesioned rats tested on PN30-35 and augmented in lesioned rats tested on PN60-65. The present data suggest that early partial loss of mesoprefrontal DA nerve terminals, resulting in a persistent decrease in tissue DA concentrations, is unlikely to result in persistent alterations in local DA release.