TY - JOUR T1 - Hippocampal Dysregulation of Neurofibromin-Dependent Pathways Is Associated with Impaired Spatial Learning in Engrailed 2 Knock-Out Mice JF - The Journal of Neuroscience JO - J. Neurosci. SP - 13281 LP - 13288 DO - 10.1523/JNEUROSCI.2894-13.2014 VL - 34 IS - 40 AU - Giovanni Provenzano AU - Luca Pangrazzi AU - Andrea Poli AU - Mattia Pernigo AU - Paola Sgadò AU - Sacha Genovesi AU - Giulia Zunino AU - Nicoletta Berardi AU - Simona Casarosa AU - Yuri Bozzi Y1 - 2014/10/01 UR - http://www.jneurosci.org/content/34/40/13281.abstract N2 - 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. ER -