title: Hippocampal dysregulation of FMRP/mGluR5 signaling in engrailed-2 knockout mice: a model of autism spectrum disorders.
abstract: Many evidences indicate that mice lacking the homeobox transcription factor engrailed-2 (En2(-/-) mice) represent a reliable model to investigate neurodevelopmental basis and gene expression changes relevant to autism spectrum disorders. Dysfunctions in fragile X mental retardation protein (FMRP), metabotropic glutamate receptor 5 (mGluR5), and GABAergic signaling pathways have been proposed as a possible pathogenic mechanism of autism spectrum disorders. Here, we exploited En2(-/-) mice to investigate hippocampal expression of FMRP, mGluR5, and GABA(A) receptor β3 subunit (GABRB3). Quantitative reverse-transcription PCR showed that all these mRNAs were significantly downregulated in En2(-/-) mice compared with wild-type littermates. Western blot and immunohistochemistry confirmed the downregulation of FMRP and GABRB3 proteins, while showing a significant increase of mGluR5 protein in the En2(-/-) hippocampus. Our results suggest that the dysregulation of FMRP-mGluR5 signaling pathway, accompanied with a downregulation of GABRB3 expression, may contribute to the 'autistic-like' features observed in En2 mice, providing possible molecular targets for future pharmacological studies.
authors.affiliation: aLaboratory of Molecular Neuropathology bLaboratory of Developmental Neurobiology, Centre for Integrative Biology (CIBIO), University of Trento, Trento cC.N.R. Neuroscience Institute, Pisa, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Provenzano
authors.forename: Paola
authors.initials: P
authors.lastname: Sgadò
authors.forename: Sacha
authors.initials: S
authors.lastname: Genovesi
authors.forename: Giulia
authors.initials: G
authors.lastname: Zunino
authors.forename: Simona
authors.initials: S
authors.lastname: Casarosa
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bozzi
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D011963:Receptors, GABA-A; C497684:Fmr1 protein, mouse; C546270:Gabrb3 protein, mouse; C578936:Grm5 protein, mouse