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

doi:10.1038/nn.3822

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

Chemistry and Biochemistry

Research output: Contribution to journal › Article › peer-review

102 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 language	English
Pages (from-to)	1583-1590
Number of pages	8
Journal	Nature Neuroscience
Volume	17
Issue number	11
DOIs	https://doi.org/10.1038/nn.3822
State	Published - Oct 28 2014

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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

@article{015ede26e3f442b09755034042bc5336,

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

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 +/{\^a} '), 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 +/{\^a} ' 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 +/{\^a} ' mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.",

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

note = "Publisher Copyright: {\textcopyright} 2014 Nature America, Inc.",

year = "2014",

month = oct,

day = "28",

doi = "10.1038/nn.3822",

language = "English",

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Molosh, AI, Johnson, PL, 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, DW & 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

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T1 - Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase

AU - Molosh, Andrei I.

AU - Johnson, Philip L.

AU - Spence, John P.

AU - Arendt, David

AU - Federici, Lauren M.

AU - Bernabe, Cristian

AU - Janasik, Steven P.

AU - Segu, Zaneer M.

AU - Khanna, Rajesh

AU - Goswami, Chirayu

AU - Zhu, Weiguo

AU - Park, Su Jung

AU - Li, Lang

AU - Mechref, Yehia S.

AU - Clapp, D. Wade

AU - Shekhar, Anantha

PY - 2014/10/28

Y1 - 2014/10/28

N2 - 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.

AB - 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.

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SP - 1583

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JO - Nature Neuroscience

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ER -

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

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