SummarySubstantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca2+ responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.

The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separationinduced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R, 4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid], showed anxiolytic activities in these models, suggesting involvement of postsynaptic mGluR1 in stress-related responses comparable with mGluR5 and mGluR2/3. Analgesic effects of FTIDC were seen in the formalin test but not in the tail immersion test. FTIDC selectively blocked methamphetamineinduced hyperlocomotion and disruption of prepulse inhibition, whereas MPEP and LY379268 did not alter those behaviors, suggesting that pharmacological blockade of mGluR1 could result in antipsychotic-like effects. FTIDC did not elicit catalepsy or impair motor functions at 10 times higher dose than doses showing antipsychotic-like action. In conclusion, blockade of mGluR1 showed antipsychotic-like effects without impairing motor functions, whereas blockade of mGluR5 and activation of mGluR2/3 did not display such activities.L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and acts on ionotropic and metabotropic glutamate receptors (mGluRs). The mGluR family consists of eight receptor subtypes, which are divided into three groups based on sequence homology, pharmacological profiles, and signal transduction pathways (De Blasi et al., 2001;Spooren et al., 2003). Group I mGluRs comprise mGluR1 and mGluR5, which are coupled with G q to activate phospholipase C, leading to the release of intracelArticle, publication date, and citation information can be found at

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