title: Cerebellar Shank2 Regulates Excitatory Synapse Density, Motor Coordination, and Specific Repetitive and Anxiety-Like Behaviors.
abstract: Shank2 is a multidomain scaffolding protein implicated in the structural and functional coordination of multiprotein complexes at excitatory postsynaptic sites as well as in psychiatric disorders, including autism spectrum disorders. While Shank2 is strongly expressed in the cerebellum, whether Shank2 regulates cerebellar excitatory synapses, or contributes to the behavioral abnormalities observed in Shank2-/-mice, remains unexplored. Here we show that Shank2-/-mice show reduced excitatory synapse density in cerebellar Purkinje cells in association with reduced levels of excitatory postsynaptic proteins, including GluD2 and PSD-93, and impaired motor coordination in the Erasmus test. Shank2 deletion restricted to Purkinje cells (Pcp2-Cre;Shank2fl/flmice) leads to similar reductions in excitatory synapse density, synaptic protein levels, and motor coordination. Pcp2-Cre;Shank2fl/flmice do not recapitulate autistic-like behaviors observed in Shank2-/-mice, such as social interaction deficits, altered ultrasonic vocalizations, repetitive behaviors, and hyperactivity. However, Pcp2-Cre;Shank2fl/flmice display enhanced repetitive behavior in the hole-board test and anxiety-like behavior in the light-dark test, which are not observed in Shank2-/-mice. These results implicate Shank2 in the regulation of cerebellar excitatory synapse density, motor coordination, and specific repetitive and anxiety-like behaviors.
  
  
  
  The postsynaptic side of excitatory synapses contains multiprotein complexes, termed the postsynaptic density, which contains receptors, scaffolding/adaptor proteins, and signaling molecules. Shank2 is an excitatory postsynaptic scaffolding protein implicated in the formation and functional coordination of the postsynaptic density and has been linked to autism spectrum disorders. Using Shank2-null mice and Shank2-conditional knock-out mice with a gene deletion restricted to cerebellar Purkinje cells, we explored functions of Shank2 in the cerebellum. We found that Shank2 regulates excitatory synapse density, motor coordination, and specific repetitive and anxiety-like behaviors, but is not associated with autistic-like social deficits or repetitive behaviors.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Seungmin
authors.identifier: 0000-0003-3970-8500
authors.initials: S
authors.lastname: Ha
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 305-701, Korea.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea, and.
authors.forename: Yi Sul
authors.identifier: 0000-0002-6310-8655
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Changuk
authors.initials: C
authors.lastname: Chung
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Ye-Eun
authors.initials: YE
authors.lastname: Yoo
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 305-701, Korea.
authors.forename: Jihye
authors.identifier: 0000-0003-2426-2470
authors.initials: J
authors.lastname: Kim
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 305-701, Korea.
authors.forename: Jiseok
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Woohyun
authors.identifier: 0000-0002-9820-4401
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Hyosang
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea, and.
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Bae
authors.affiliation: Center for Functional Connectomics, Korea Institute of Science and Technology, Seoul 136-791, Korea kime@kaist.ac.kr keiko@kist.re.kr.
authors.forename: Keiko
authors.initials: K
authors.lastname: Tanaka-Yamamoto
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea, kime@kaist.ac.kr keiko@kist.re.kr.|Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 305-701, Korea.
authors.forename: Eunjoon
authors.identifier: 0000-0001-5518-6584
authors.initials: E
authors.lastname: Kim
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001522:Behavior, Animal / Q000502:physiology; D002452:Cell Count; D002531:Cerebellum / Q000503:physiopathology*; D012090:Cumulative Trauma Disorders / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011597:Psychomotor Performance / Q000502:physiology*; D013569:Synapses / Q000473:pathology* / Q000502:physiology
chemical_list: D009419:Nerve Tissue Proteins; C488222:Shank2 protein, mouse
keywords: GluD2; Purkinje cell; Shank2; autism; cerebellum; excitatory synapse