Corinne M. Spencer

Local translation of proteins in distal dendrites is thought to support synaptic structural plasticity. We have previously shown that metabotropic glutamate receptor (mGluR1) stimulation initiates a phosphorylation cascade, triggering rapid association of some mRNAs with translation machinery near synapses, and leading to protein synthesis. To determine the identity of these mRNAs, a cDNA library produced from distal nerve processes was used to screen synaptic polyribosome-associated mRNA. We identified mRNA for the fragile X mental retardation protein (FMRP) in these processes by use of synaptic subcellular fractions, termed synaptoneurosomes. We found that this mRNA associates with translational complexes in synaptoneurosomes within 1-2 min after mGluR1 stimulation of this preparation, and we observed increased expression of FMRP after mGluR1 stimulation. In addition, we found that FMRP is associated with polyribosomal complexes in these fractions. In vivo, we observed FMRP immunoreactivity in spines, dendrites, and somata of the developing rat brain, but not in nuclei or axons. We suggest that rapid production of FMRP near synapses in response to activation may be important for normal maturation of synaptic connections.

About 35% of patients with 22q11 deletion syndrome (22q11DS), which includes DiGeorge and velocardiofacial syndromes, develops psychiatric disorders, mainly schizophrenia and bipolar disorder. We previously reported that mice carrying a multigene deletion (Df1) that models 22q11DS have reduced prepulse inhibition (PPI), a behavioral abnormality and schizophrenia endophenotype. Impaired PPI is associated with several psychiatric disorders, including those that occur in 22q11DS, and recently, reduced PPI was reported in children with 22q11DS. Here, we have mapped PPI deficits in a panel of mouse mutants that carry deletions that partially overlap with Df1 and have defined a PPI critical region encompassing four genes. We then used single-gene mutants to identify the causative genes. We show that PPI deficits in Df1/+ mice are caused by haploinsufficiency of two genes, Tbx1 and Gnb1l. Mutation of either gene is sufficient to cause reduced PPI. Tbx1 is a transcription factor, the mutation of which is sufficient to cause most of the physical features of 22q11DS, but the gene had not been previously associated with the behavioral/psychiatric phenotype. A likely role for Tbx1 haploinsufficiency in psychiatric disease is further suggested by the identification of a family in which the phenotypic features of 22q11DS, including psychiatric disorders, segregate with an inactivating mutation of TBX1. One family member has Asperger syndrome, an autistic spectrum disorder that is associated with reduced PPI. Thus, Tbx1 and Gnb1l are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes for psychiatric disease in the wider population.

The loss of fragile X mental retardation (FMR1) gene function causes fragile X syndrome (FXS), a common mental retardation syndrome. Anxiety and abnormal social behaviors are prominent features of FXS in humans. To better understand the role of FMR1 in these behaviors, we analyzed anxiety-related and social behaviors in Fmr1 knockout (KO) mice. In the mirrored chamber test, Fmr1 KO mice showed greater aversion to the central mirrored chamber than wild-type (WT) littermates, suggesting increased anxiety-like responses to reflected images of mice. Fmr1 KO mice exhibited abnormal social interactions in a tube test of social dominance, winning fewer matches than WT littermates. In a partition test, Fmr1 KO mice had normal levels of social interest and social recognition. However, during direct interaction tests, Fmr1 KO mice showed significant increases in sniffing behaviors. We further tested the influence of environmental familiarity on the social responses of Fmr1 KO mice to unfamiliar partners. In unfamiliar partitioned cages, Fmr1 KO mice did not differ from WT mice in investigation of unfamiliar partners. However, in familiar partitioned cages, Fmr1 KO mice showed less investigation of a newly introduced partner during the first 5 min and more investigation during the last 5 min of a 20-min partition test, behaviors consistent with initial social anxiety followed by enhanced social investigation. Our findings indicate that the loss of Fmr1 gene function results in altered anxiety and social behavior in mice and demonstrate that the Fmr1 KO mouse is a relevant animal model for the abnormal social responses seen in FXS.