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(+/-)), 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(+/-) 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(+/-) mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.
authors.affiliation: 1] Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA. [2] Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Molosh
authors.affiliation: 1] Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA. [2] Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA. [3] Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Johnson
authors.affiliation: 1] Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA. [2] Program in Medical Neurosciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Spence
authors.affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: David
authors.initials: D
authors.lastname: Arendt
authors.affiliation: 1] Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA. [2] Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA. [3] Program in Medical Neurosciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Federici
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bernabe
authors.affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Janasik
authors.affiliation: Department of Chemistry, METACyt Biochemical Analysis Center, Indiana University, Bloomington, Indiana, USA.
authors.forename: Zaneer M
authors.initials: ZM
authors.lastname: Segu
authors.affiliation: 1] Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA. [2] Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Chirayu
authors.initials: C
authors.lastname: Goswami
authors.affiliation: 1] Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA. [2] Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Chemistry, METACyt Biochemical Analysis Center, Indiana University, Bloomington, Indiana, USA.
authors.forename: Yehia S
authors.initials: YS
authors.lastname: Mechref
authors.affiliation: 1] Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA. [2] Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.affiliation: 1] Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA. [2] Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA. [3] Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA. [4] Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D002659:Child Development Disorders, Pervasive / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000502:physiology*; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D025542:Neurofibromin 1 / Q000172:deficiency / Q000378:metabolism*; D012919:Social Behavior; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D025542:Neurofibromin 1; D054462:p21-Activated Kinases