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

Andrei I. Molosh, Philip 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. Clapp, Anantha Shekhar

Research output: Contribution to journalArticle

52 Citations (Scopus)

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

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p21-Activated Kinases
Amygdala
Neurofibromatosis 1
Social Behavior
Synaptic Transmission
gamma-Aminobutyric Acid
Glutamic Acid
Disintegrins
HSP70 Heat-Shock Proteins
Long-Term Potentiation
Metalloproteases
Frontal Lobe
Mitogen-Activated Protein Kinases
Protein Kinases
Alleles
Pharmacology
Neurons
Social Learning
Genes
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. / Molosh, Andrei I.; Johnson, Philip; Spence, John P.; Arendt, David; Federici, Lauren M.; Bernabe, Cristian; Janasik, Steven P.; Segu, Zaneer M.; Khanna, Rajesh; Goswami, Chirayu; Zhu, Weiguo; Park, Su Jung; Li, Lang; Mechref, Yehia S.; Clapp, D.; Shekhar, Anantha.

In: Nature Neuroscience, Vol. 17, No. 11, 28.10.2014, p. 1583-1590.

Research output: Contribution to journalArticle

Molosh, AI, Johnson, P, Spence, JP, Arendt, D, Federici, LM, Bernabe, C, Janasik, SP, Segu, ZM, Khanna, R, Goswami, C, Zhu, W, Park, SJ, Li, L, Mechref, YS, Clapp, D & Shekhar, A 2014, 'Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase', Nature Neuroscience, vol. 17, no. 11, pp. 1583-1590. https://doi.org/10.1038/nn.3822
Molosh, Andrei I. ; Johnson, Philip ; Spence, John P. ; Arendt, David ; Federici, Lauren M. ; Bernabe, Cristian ; Janasik, Steven P. ; Segu, Zaneer M. ; Khanna, Rajesh ; Goswami, Chirayu ; Zhu, Weiguo ; Park, Su Jung ; Li, Lang ; Mechref, Yehia S. ; Clapp, D. ; Shekhar, Anantha. / Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. In: Nature Neuroscience. 2014 ; Vol. 17, No. 11. pp. 1583-1590.
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