Mapk-Erk activation in an animal model of social deficits shows a possible link to autismReport as inadecuate

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Molecular Autism

, 5:57

First Online: 22 December 2014Received: 10 August 2014Accepted: 08 October 2014


BackgroundThere is converging preclinical and clinical evidence to suggest that the extracellular signal-regulated kinase ERK signaling pathway may be dysregulated in autism spectrum disorders.

MethodWe evaluated Mapk-Erk1-2, cellular proliferation and apoptosis in BTBR mice, as a preclinical model of Autism. We had previously generated 410 F2 mice from the cross of BTBR with B6. At that time, six different social behaviors in all F2 mice were evaluated and scored. In this study, eight mice at each extreme of the social behavioral spectrum were selected and the expression and activity levels of Mapk-Erk in the prefrontal cortex and cerebellum of these mice were compared. Finally, we compared the Mapk-Erk signaling pathway in brain and lymphocytes of the same mice, testing for correlation in the degree of kinase activation across these separate tissues.

ResultsLevels of phosphorylated Erk p-Erk were significantly increased in the brains of BTBR versus control mice. We also observed a significant association between juvenile social behavior and phosphorylated mitogen-activated protein kinase kinase p-Mek and p-Erk levels in the prefrontal cortex but not in the cerebellum. In contrast, we did not find a significant association between social behavior and total protein levels of either Mek or Erk. We also tested whether steady-state levels of Erk activation in the cerebral cortex in individual animals correlated with levels of Erk activation in lymphocytes, finding a significant relationship for this signaling pathway.

ConclusionThese observations suggest that dysregulation of the ERK signaling pathway may be an important mediator of social behavior, and that measuring activation of this pathway in peripheral lymphocytes may serve as a surrogate marker for central nervous system CNS ERK activity, and possibly autistic behavior.

AbbreviationsASDAutism spectrum disorders

B6C57BL-6 J


CNSCentral nervous system, CNV, Copy number variant


ERKExtracellular signal-regulated kinase

GEGanglionic eminence

HRPhorseradish peroxidase

LTDLong-term depression

LTPLong-term potentiation

MAPKMitogen-activated protein kinase

MEKMitogen-activated protein kinase kinase

Pax6Paired Box 6

PBSPhosphate buffered saline

p-ERKPhosphorylated extracellular signal-regulated kinase

PH3Phospho-histone H3

RBCRed blood cell

t-ERKTotal protein level of ERK

Tbr2T-Box Brain Protein 2.

Electronic supplementary materialThe online version of this article doi:10.1186-2040-2392-5-57 contains supplementary material, which is available to authorized users.

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Author: Alireza Faridar - Dorothy Jones-Davis - Eric Rider - Jiang Li - Ilan Gobius - Laura Morcom - Linda J Richards - Saunak Se


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