PT  - JOURNAL ARTICLE
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
TI  - Hippocampal Dysregulation of Neurofibromin-Dependent Pathways Is Associated with Impaired Spatial Learning in Engrailed 2 Knock-Out Mice
AID  - 10.1523/JNEUROSCI.2894-13.2014
DP  - 2014 Oct 01
TA  - The Journal of Neuroscience
PG  - 13281--13288
VI  - 34
IP  - 40
4099  - http://www.jneurosci.org/content/34/40/13281.short
4100  - http://www.jneurosci.org/content/34/40/13281.full
SO  - J. Neurosci.2014 Oct 01; 34
AB  - 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.