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 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 may 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.

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

“…Perseverative behavior is defined as choosing the previously rewarded stimulus location instead of choosing the currently active location. Mice with mutations in genes coding for the muscarinic acetylcholine receptor M1 and the NMDA receptor subunit Grin1 displayed perseverative deficits in 5-CSRTT (Bartko et al 2011; Finlay et al 2014). Despite the broad range of autism-relevant phenotypes displayed by BTBR mice, BTBR did not show perseverative behavior as assessed by the 5-CSRTT (McTighe et al 2013).…”

Reversal of social deficits by subchronic oxytocin in two autism mouse models

“…There is growing evidence that alterations in NMDA receptor signaling play a role in ASD and other neurodevelopmental disorders (for recent reviews, see Burnashev et al 2015; Lee et al 2015), including reports that autism candidate genes, such as NEUROLIGIN-1 and SHANK3 , serve as regulators of NMDA receptor function (Budreck et al 2013; Duffney et al 2013). Mice with reduced Grin1 expression recapitulate many ASD features, including overt social deficits, inappropriate social interaction, abnormal repetitive behavior, self-injurious responses, and impaired sensorimotor gating (Billingslea et al 2014; Duncan et al, 2004, Finlay et al 2015; Gandal et al, 2012, Milenkovic et al, 2014; Mohn et al, 1999, Moy et al, 2008a, 2012, 2014; Saunders et al 2013). We determined the effects of oxytocin on social deficits, reduced prepulse inhibition, and hyperactivity in Grin1 knockdown mice.…”

A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder

“…They are heterotetrameric proteins typically composed of two compulsory GRIN1 subunits linked to a combination of GRIN2 (A-D) or GRIN3 (A-B) subunits [Paoletti, 2011], potentially alongside a glutamate-binding protein, GRINA [Chen et al, 1988]. NMDA receptors have been implicated in impulsivity and aggression [Chang et al, 2015; Finlay et al, 2015], and three NMDA receptor genes ( GRIN1, GRIN2C, GRINA ) have altered expression levels in postmortem brains of suicide completers [Higgs et al, 2006]. These features make NMDA receptors and their interacting partners, such as the NRXN and NLGN gene families, prime candidates for involvement in the impulsive aggression phenotype and suicidal behavior.…”