title: Hippocampal dysregulation of neurofibromin-dependent pathways is associated with impaired spatial learning in engrailed 2 knock-out mice.
abstract: Genome-wide association studies indicated the homeobox-containing transcription factor Engrailed-2 (En2) as a candidate gene for autism spectrum disorders (ASD). Accordingly, En2 knock-out (En2(-/-)) mice show anatomical and behavioral "ASD-like" features, including decreased sociability and learning deficits. The molecular pathways underlying these deficits in En2(-/-) mice are not known. Deficits in signaling pathways involving neurofibromin and extracellular-regulated kinase (ERK) have been associated with impaired learning. Here we investigated the neurofibromin-ERK cascade in the hippocampus of wild-type (WT) and En2(-/-) mice before and after spatial learning testing. When compared with WT littermates, En2(-/-) mice showed impaired performance in the Morris water maze (MWM), which was accompanied by lower expression of the activity-dependent gene Arc. Quantitative RT-PCR, immunoblotting, and immunohistochemistry experiments showed a marked downregulation of neurofibromin expression in the dentate gyrus of both naive and MWM-treated En2(-/-) mice. ERK phosphorylation, known to be induced in the presence of neurofibromin deficiency, was increased in the dentate gyrus of En2(-/-) mice after MWM. Treatment of En2(-/-) mice with lovastatin, an indirect inhibitor of ERK phosphorylation, markedly reduced ERK phosphorylation in the dentate gyrus, but was unable to rescue learning deficits in MWM-trained mutant mice. Further investigation is needed to unravel the complex molecular mechanisms linking dysregulation of neurofibromin-dependent pathways to spatial learning deficits in the En2 mouse model of ASD.
authors.affiliation: Molecular Neuropathology and.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Provenzano
authors.affiliation: Molecular Neuropathology and.
authors.forename: Luca
authors.initials: L
authors.lastname: Pangrazzi
authors.affiliation: C.N.R. Neuroscience Institute, 56124 Pisa, Italy, and.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0001-7163-9627
authors.initials: A
authors.lastname: Poli
authors.affiliation: Molecular Neuropathology and.
authors.forename: Mattia
authors.identifier: http://orcid.org/0000-0003-0881-1863
authors.initials: M
authors.lastname: Pernigo
authors.affiliation: Molecular Neuropathology and.
authors.forename: Paola
authors.initials: P
authors.lastname: Sgadò
authors.affiliation: Molecular Neuropathology and.
authors.forename: Sacha
authors.initials: S
authors.lastname: Genovesi
authors.affiliation: Molecular Neuropathology and.
authors.forename: Giulia
authors.initials: G
authors.lastname: Zunino
authors.affiliation: C.N.R. Neuroscience Institute, 56124 Pisa, Italy, and Department of Neuroscience and Psychology, University of Florence, 50121 Florence, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Berardi
authors.affiliation: Developmental Neurobiology Laboratory, Centre for Integrative Biology (CIBIO), University of Trento, Trento 38100, Italy, C.N.R. Neuroscience Institute, 56124 Pisa, Italy, and.
authors.forename: Simona
authors.initials: S
authors.lastname: Casarosa
authors.affiliation: Molecular Neuropathology and C.N.R. Neuroscience Institute, 56124 Pisa, Italy, and bozzi@science.unitn.it.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bozzi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007859:Learning Disabilities / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008148:Lovastatin / Q000627:therapeutic use; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D025542:Neurofibromin 1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D000099266:Engrailed 2 Protein
chemical_list: D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D012333:RNA, Messenger; D000099266:Engrailed 2 Protein; C092069:activity regulated cytoskeletal-associated protein
keywords: Morris water maze; autism; hippocampus; kinase; neurodevelopmental disorder; neurofibromatosis