Neuroligin-3 is a member of the class of cell adhesion proteins that mediate synapse development and have been implicated in autism. Mice with the human R451C mutation (NL3), identical to the point mutation found in two brothers with autism spectrum disorders, were generated and phenotyped in multiple behavioral assays with face validity to the diagnostic symptoms of autism. No differences between NL3 and their wildtype littermate controls (WT) were detected on measures of juvenile reciprocal social interaction, adult social approach, cognitive abilities, and resistance to change in a spatial habit, findings which were replicated in several cohorts of males and females. Physical and procedural abilities were similar across genotypes on measures of general health, sensory abilities, sensorimotor gating, motor functions, and anxiety-related traits. Minor developmental differences were detected between NL3 and WT, including slightly different rates of somatic growth, slower righting reflexes at postnatal days 2−6, faster homing reflexes in females, and more vocalizations on postnatal day 8 in males. Significant differences in NL3 adults included somewhat longer latencies to fall from the rotarod, less vertical activity in the open field, and less acoustic startle to high decibel tones. The humanized R451C mutation in mice did not result in apparent autism-like phenotypes, but produced detectable functional consequences that may be interpreted in terms of physical development and/or reduced sensitivity to stimuli.

Abnormal immune responses have been reported to be associated with autism. A number of studies showed that cytokines were increased in the blood, brain, and cerebrospinal fluid of autistic subjects. Elevated IL-6 in autistic brain has been a consistent finding. However, the mechanisms by which IL-6 may be involved in the pathogenesis of autism are not well understood. Here we show that mice with elevated IL-6 in the brain display many autistic features, including impaired cognitive abilities, deficits in learning, abnormal anxiety traits and habituations, as well as decreased social interactions. IL-6 elevation caused alterations in excitatory and inhibitory synaptic formations and disrupted the balance of excitatory/inhibitory synaptic transmissions. IL-6 elevation also resulted in an abnormal change in the shape, length and distributing pattern of dendritic spines. These findings suggest that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity.

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Animal models of human diseases are in widespread use for biomedical research. Mouse models with a mutation in a single gene or multiple genes are excellent research tools for understanding the role of a specific gene in the etiology of a human genetic disease. Ideally, the mouse phenotypes will recapitulate the human phenotypes exactly. However, exact matches are rare, particularly in mouse models of neuropsychiatric disorders. This article summarizes the current strategies for optimizing the validity of a mouse model of a human brain dysfunction. We address the common question raised by molecular geneticists and clinical researchers in psychiatry, "what is a 'good enough' mouse model"? Keywords mouse; model; behavior; phenotyping FUNDAMENTAL CONSIDERATIONSAs molecular geneticists generate mutant models of human genetic diseases, a host of methodological questions arise. What are the criteria necessary to define the model organism? Which assays are most appropriate for phenotyping the disease model? How many tests are necessary, how many replications must be conducted, and which controls are essential? In the case of neuropsychiatric disorders, which behavioral assays are sufficiently analogous to the behavioral symptoms of the human syndrome? This overview discusses the basic concepts inherent in phenotyping animal models of human neuropsychiatric disorders.Three criteria are commonly used to validate an animal model. (1) Construct validity incorporates a conceptual analogy to the cause of the human disease. Mutant mice with a targeted mutation in a gene implicated in a neuropsychiatric disorder have reasonable construct validity for that inactivation or polymorphism of the human gene. Neuroanatomical lesions, prenatal drug exposures, and environmental toxins offer other examples of putative causes of human diseases that can be replicated in animal models. For example, a mouse model of schizophrenia could test the hypothesis that the gene COMT confers susceptibility to schizophrenia by knocking out the COMT gene in the mouse genome O'Tuathaigh et al., 2007], or could evaluate a knockin of the humanized DISC1 polymorphism found in some schizophrenic patients [Pletnikov et al., 2008]. (2 NIH Public Access Author ManuscriptAm J Med Genet B Neuropsychiatr Genet. Author manuscript; available in PMC 2010 August 3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript biochemical, and neurophysiological markers for a given disease. The temporal progression of a neurodevelopmental or neurodegenerative disease is approximated in the animal model by repeating assays to generate a longitudinal profile at appropriate ages. For example, autism is diagnosed by three behavioral criteria, in which aberrant reciprocal social interaction is the primary diagnostic symptom. Our automated three chambered social approach task assays aspects of sociability in mice that are most relevant to the first diagnostic symptom of autism, and can be used repeatedly in the same animals for longitudinal analyses of...

BackgroundStudies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice.MethodsDams were fed FA either at 0.4 mg or 4 mg/kg diet throughout the pregnancy and the resulting pups were maintained on the diet throughout experimentation. Newborn pups brain cerebral hemispheres were used for microarray analysis. To confirm alteration of several genes, quantitative RT-PCR (qRT-PCR) and Western blot analyses were performed. In addition, various behavior assessments were conducted on neonatal and adult offspring.ResultsResults from microarray analysis suggest that the higher dose of FA supplementation during gestation alters the expression of a number of genes in the newborns’ cerebral hemispheres, including many involved in development. QRT-PCR confirmed alterations of nine genes including down-regulation of Cpn2, Htr4, Zfp353, Vgll2 and up-regulation of Xist, Nkx6-3, Leprel1, Nfix, Slc17a7. The alterations in the expression of Slc17a7 and Vgll2 were confirmed at the protein level. Pups exposed to the higher dose of FA exhibited increased ultrasonic vocalizations, greater anxiety-like behavior and hyperactivity. These findings suggest that although FA plays a significant role in mammalian cellular machinery, there may be a loss of benefit from higher amounts of FA. Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior.