Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self‐grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety‐like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3‐hydroxylase, an enzyme‐regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism‐like behavioral phenotypes. Robust and selective social deficits, repetitive self‐grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.

Mice are a nocturnal species, whose social behaviors occur primarily during the dark phase of the circadian cycle. However, laboratory rodents are frequently tested during their light phase, for practical reasons. We investigated the question of whether light phase testing presents a methodological pitfall for investigating mouse social approach behaviors. Three lines of mice were systematically compared. One cohort of each line was raised in a conventional lighting schedule and tested during the light phase, under white light illumination; another cohort was raised in a reverse lighting schedule and tested during their dark phase, under dim red light. Male C57BL/6J (B6) displayed high levels of sociability in our three-chambered automated social approach task when tested in either phase. BTBR T+ tf/J (BTBR) displayed low levels of sociability in either phase. Five cohorts of vasopressin receptor subtype 1b (Avpr1b) null mutants, heterozygotes, and wildtype littermate controls were tested in the same social approach paradigm: three in the dark phase and two in the light phase. All three genotypes displayed normal sociability in four out of the five replications. In the juvenile play test, testing phase had no effect on play soliciting behaviors in Avpr1b mice, but had modest effects on nose sniff and huddling. Taken together, these findings indicate that testing phase is not a crucial factor for studying some forms of social approach in juvenile and adult mice.

The neuropeptides oxytocin and vasopressin have been implicated in rodent social and affiliative behaviors, including social bonding, parental care, social recognition, social memory, vocalizations, territoriality, and aggression, as well as components of human social behaviors and the etiology of autism. Previous investigations of mice with various manipulations of the oxytocin and vasopressin systems reported unusual levels of ultrasonic vocalizations in social settings. We employed a vasopressin 1b receptor (Avpr1b) knockout mouse to evaluate the role of the vasopressin 1b receptor subtype in the emission of ultrasonic vocalizations in adult and infant mice. Avpr1b null mutant female mice emitted fewer ultrasonic vocalizations, and their vocalizations were generally at lower frequencies, during a resident-intruder test. Avpr1b null mutant pups emitted ultrasonic vocalizations similar to heterozygote and wildtype littermates when separated from the nest on postnatal days 3, 6, 9, and 12. However, maternal potentiation of ultrasonic vocalizations in Avpr1b null and heterozygote mutants was absent, when tested at postnatal day 9. These results indicate that Avpr1b null mutant mice are impaired in the modulation of ultrasonic vocalizations within different social contexts at infant and adult ages.

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.

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Pharmacological studies indicate that vasoactive intestinal peptide (VIP) may be necessary for normal embryonic development in the mouse. For example, VIP antagonist treatment before embryonic day 11 resulted in developmental delays, growth restriction, modified adult brain chemistry and reduced social behavior. Here, developmental milestones, growth, and social behaviors of neonates of VIP-deficient mothers (VIP +/-) mated to VIP +/- males were compared with the offspring of wild type mothers (VIP +/+) mated to VIP +/+ and +/- males, to assess the contributions of both maternal and offspring VIP genotype. Regardless of their own genotype, all offsprings of VIP-deficient mothers exhibited developmental delays. No delays were seen in the offspring of wild type mothers, regardless of their own genotype. Body weights were significantly reduced in offspring of VIP-deficient mothers, with VIP null (-/-) the most affected. Regardless of genotype, all offspring of VIP-deficient mothers expressed reduced maternal affiliation compared with wild type offspring of wild type mothers; +/- offspring of wild type mothers did not differ in maternal affiliation from their wild type littermates. Play behavior was significantly reduced in all offsprings of VIP-deficient mothers. Maternal behavior did not differ between wild type and VIP-deficient mothers, and cross-fostering of litters did not change offspring development, indicating that offspring deficits were induced prenatally. This study illustrated that the VIP status of a pregnant mouse had a greater influence on the growth, development and behavior of her offspring than the VIP genotype of the offspring themselves. Deficiencies were apparent in +/+, +/- and -/- offspring born to VIP-deficient mothers; no deficiencies were apparent in +/- offspring born to normal mothers. These results underscore the significant contribution of the uterine environment to normal development and indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders with social behavior deficits such as autism.

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