ABSTRACT
Cerebellar dysfunction has been linked to autism spectrum disorders (ASDs). Although cerebellar pathology has been observed in individuals with fragile X syndrome (FXS) and in mouse models of the disorder, a cerebellar functional contribution to ASD-relevant behaviors in FXS has yet to be fully characterized. In this study, we demonstrate a critical cerebellar role for Fmr1 (fragile X messenger ribonucleoprotein 1) in ASD-relevant behaviors. First, we identify reduced social behaviors, sensory hypersensitivity, and cerebellar dysfunction, with loss of cerebellar Fmr1. We then demonstrate that cerebellar-specific expression of Fmr1 is sufficient to impact social, sensory, cerebellar dysfunction, and cerebro-cortical hyperexcitability phenotypes observed in global Fmr1 mutants. Moreover, we demonstrate that targeting the ASD-implicated cerebellar region Crus1 ameliorates behaviors in both cerebellar-specific and global Fmr1 mutants. Together, these results demonstrate a critical role for the cerebellar contribution to FXS-related behaviors, with implications for future therapeutic strategies.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Cerebellar Diseases , Fragile X Syndrome , Animals , Mice , Fragile X Syndrome/metabolism , Autistic Disorder/genetics , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/metabolism , Disease Models, Animal , Mice, KnockoutABSTRACT
OBJECTIVE: Globally, more than 200 million people live at risk of the neglected tropical disease schistosomiasis (or snail fever). Larval schistosomes require the presence of specific snail species that act as intermediate hosts, supporting their multiplication and transformation into forms that can infect humans. This project was designed to generate a transcriptome from the central nervous system (CNS) of Biomphalaria alexandrina, the major intermediate host for Schistosoma mansoni in Egypt. RESULTS: A transcriptome was generated from five pooled central nervous systems dissected from uninfected specimens of B. alexandrina. Raw Illumina RNA-seq data (~ 20.3 million paired end reads of 150 base pairs length each) generated a transcriptome consisting of 144,213 transcript elements with an N50 contig size of 716 base pairs. Orthologs of 15,246 transcripts and homologs for an additional 16,810 transcripts were identified in the UniProtKB/Swiss-Prot database. The B. alexandrina CNS transcriptome provides a resource for future research exploring parasite-host interactions in a simpler nervous system. Moreover, increased understanding of the neural signaling mechanisms involved in the response of B. alexandrina to infection by S. mansoni larvae could lead to novel and highly specific strategies for the control of snail populations.
