Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase

Andrei I. Molosh, Philip L. Johnson, John P. Spence, David Arendt, Lauren M. Federici, Cristian Bernabe, Steven P. Janasik, Zaneer M. Segu, Rajesh Khanna, Chirayu Goswami, Weiguo Zhu, Su Jung Park, Lang Li, Yehia S. Mechref, D. Wade Clapp, Anantha Shekhar

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1 +/â '), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1 +/â ' mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these amygdala disruptions were normalized by the additional deletion of the p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1 +/â ' mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.

Original languageEnglish (US)
Pages (from-to)1583-1590
Number of pages8
JournalNature Neuroscience
Volume17
Issue number11
DOIs
StatePublished - Oct 28 2014

ASJC Scopus subject areas

  • Neuroscience(all)

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    Molosh, A. I., Johnson, P. L., Spence, J. P., Arendt, D., Federici, L. M., Bernabe, C., Janasik, S. P., Segu, Z. M., Khanna, R., Goswami, C., Zhu, W., Park, S. J., Li, L., Mechref, Y. S., Clapp, D. W., & Shekhar, A. (2014). Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nature Neuroscience, 17(11), 1583-1590. https://doi.org/10.1038/nn.3822