Preweaning Sensorimotor Deficits and Adolescent Hypersociability in <b><i>Grin1</i></b> Knockdown Mice

Abstract

Mice with knockdown of the N-methyl-<smlcap>d</smlcap>-aspartate (NMDA) receptor NR1 subunit, encoded by the gene Grin1, have been investigated as a model for the intrinsic NMDA hypofunction hypothesized for schizophrenia. Previous work has shown that adult Grin1 mutant mice have overt deficits in habituation and sensorimotor gating, exaggerated reactivity to environmental stimuli, reduced social approach, and other alterations that reflect behavioral manifestations of schizophrenia. In humans, the emergence of overt symptoms of the disorder typically occurs in adolescence or early adulthood, suggesting a role for aberrant maturation of NMDA receptor signaling in symptom onset. The following study evaluated Grin1 mutant mice for abnormal behavioral phenotypes during the preweaning, adolescent, and adult periods. Measures included open field activity, prepulse inhibition of acoustic startle responses, and social preference in a three-chamber choice task. Mice from the C57BL/6J inbred strain, one of the parental strains for the Grin1 line, were also tested. The results showed that developmental reduction of NMDA receptor function led to significant alterations in behavior during the second and third weeks of life, including exaggerated startle responses and sensorimotor gating deficits on postnatal day 13, and pronounced hypersociability in adolescence. Male Grin1 mutant mice were more susceptible than female mice to the detrimental effects of decreased NMDA signaling. Overall, these findings provide evidence that reduced Grin1 function leads to abnormal phenotypes in the preweaning period, and that deficient NMDA signaling can lead to both overt hypersociability or marked asociality, dependent upon sex and age.

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

“…Thus, we evaluated the ability of DPFE to reverse the behavioral deficits in NR1KD mice, a genetic model of NMDAR hypofunction (Ramsey, 2009), to avoid potential confounds observed with NMDAR antagonist challenge models. NR1KD mice display an approximately 90% decrease in functional NMDARs in limbic and forebrain regions and corresponding behavioral alterations, including hyperlocomotor activity and performance deficits in social interaction and cognition (Dzirasa et al, 2009;Halene et al, 2009;Ramsey, 2009;Moy et al, 2012), comparable to those induced with NMDAR antagonists. Treatment with DPFE reversed the hyperlocomotor activity observed in the NR1KD mice similar to the effects observed with clinically available antipsychotics (Mohn et al, 1999).…”

Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke

“…We calculated the percentage of beam breaks in the center zone (16/3″ × 16/3″) compared to the total as a measure of anxiety-like behavior. Importantly, OFT tests can be administered at several time points to view trends without hindrance by habituation (Moy et al, 2012). …”

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

“…Grin1 neo/neo mice engineered with a neomycin resistance gene (neo) in intron 20 of the Grin1 locus and Grin1 +/+ littermate controls were generated from heterozygous breeder pairs, as previously described (Mohn et al, 1999; Moy et al, 2012). Experimenters conducting the behavioral tests were blind to genotype.…”

“…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.…”