Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice

Reduced glutamic acid decarboxylase (GAD)67 expression may be causally involved in the development of social withdrawal in neuropsychiatric states such as autism, schizophrenia and bipolar disorder. In this study, we report disturbance of social behavior in male GAD67 haplodeficient mice. GAD67^+/? mice, compared to GAD67^+/+ littermates, show reduced sociability and decreased intermale aggression, but normal nest building and urine marking behavior, as well as unchanged locomotor activity and anxiety‐like behavior. Moreover, the mutants display a reduced sensitivity to both social and non‐social odors, indicating a disturbance in the detection and/or processing of socially relevant olfactory stimuli. Indeed, we observed reduced activation of the lateral septum, medial preoptic area, bed nucleus of the stria terminalis, medial and cortical amygdala upon exposure of GAD67^+/? mice to social interaction paradigm, as indicated by c‐Fos immunohistochemistry. These data suggest a disturbance of stimulus processing in the brain circuitry controlling social behavior in GAD67^+/? mice, which may provide a useful model for studying the impact of a reduced GAD67 expression on alterations of social behavior related to neuropsychiatric disorders .     

Npas4 deficiency and prenatal stress interact to affect social recognition in mice

Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia have an expansive array of reported genetic and environmental contributing factors. However, none of these factors alone can account for a substantial proportion of cases of either disorder. Instead, many gene‐by‐environment interactions are responsible for neurodevelopmental disturbances that lead to these disorders. The current experiment used heterozygous knock‐out mice to examine a potential interaction between 2 factors commonly linked to neurodevelopmental disorders and cognitive deficit: imbalanced excitatory/inhibitory signaling in the cortex and prenatal stress (PNS) exposure. Both of these factors have been linked to disrupt GABAergic signaling in the prefrontal cortex (PFC), a common feature of neurodevelopmental disorders. The neuronal PAS domain protein 4 (Npas4) gene is instrumental in regulation of the excitatory/inhibitory balance in the cortex and hippocampus in response to activation. Npas4 heterozygous and wild‐type male and female mice were exposed to either PNS or standard gestation, then evaluated during adulthood in social and anxiety behavioral measures. The combination of PNS and Npas4 deficiency in male mice impaired social recognition. This behavioral deficit was associated with decreased parvalbumin and cFos protein expression in the infralimbic region of the PFC following social stimulation in Npas4 heterozygous males. In contrast, females displayed fewer behavioral effects and molecular changes in PFC in response to PNS and decreased Npas4.     

Modulation of social behavior and dominance status by chronic pain in mice

The potential influence of pain on social behavior in laboratory animals has rarely been evaluated. Using a new assay of social behavior, the tube co‐occupancy test (TCOT), we assess propinquity—the tendency to maintain close physical proximity—in mice exposed to pain using subcutaneous zymosan or spared nerve injury as noxious stimuli. Our previous experience with the TCOT showed that outbred mouse sibling dyads show higher levels of tube co‐occupancy than stranger dyads. We find here that long‐lasting pain from spared nerve injury given to both mice in the dyad abolishes this effect of familiarity, such that strangers also display high levels of propinquity. We performed a separate experiment to assess the effect on dominance behavior of nerve injury to one or both mice of a dyad in which relative dominance status had been previously established via the confrontation tube test. We find that neuropathic pain given only to the dominant mouse reverses the relationship in male but not female mice, such that the previously subordinate mouse becomes dominant. These observations bolster the scant but growing evidence that pain can robustly affect social behavior in animals.     

Mouse knockout of guanylyl cyclase C: Recognition memory deficits in the absence of activity changes

Guanylyl cyclase C (GC‐C) is found in brain regions where dopamine is expressed. We characterized a mouse in which GC‐C was knocked out (KO) that was reported to be a model of attention deficit hyperactivity disorder (ADHD). We re‐examined this model and controlled for litter effects, used 16 to 23 mice per genotype per sex and assessed an array of behavioral and neurochemical outcomes. GC‐C KO mice showed no phenotypic differences from wild‐type mice on most behavioral tests, or on striatal or hippocampal monoamines, and notably no evidence of an ADHD‐like phenotype. KO mice were impaired on novel object recognition, had decreased tactile startle but not acoustic startle, and females had increased latency on cued training trials in the Morris water maze, but not hidden platform spatial learning trials. Open‐field activity showed small differences in females but not males. The data indicate that the GC‐C KO mouse with proper controls and sample sizes has a moderate cognitive and startle phenotype but has no ADHD‐like phenotype.