title: Roles of Cbln1 in Non-Motor Functions of Mice.
abstract: The cerebellum is thought to be involved in cognitive functions in addition to its well established role in motor coordination and motor learning in humans. Cerebellin 1 (Cbln1) is predominantly expressed in cerebellar granule cells and plays a crucial role in the formation and function of parallel fiber-Purkinje cell synapses. Although genes encoding Cbln1 and its postsynaptic receptor, the delta2 glutamate receptor (GluD2), are suggested to be associated with autistic-like traits and many psychiatric disorders, whether such cognitive impairments are caused by cerebellar dysfunction remains unclear. In the present study, we investigated whether and how Cbln1 signaling is involved in non-motor functions in adult mice. We show that acquisition and retention/retrieval of cued and contextual fear memory were impaired in Cbln1-null mice. In situ hybridization and immunohistochemical analyses revealed that Cbln1 is expressed in various extracerebellar regions, including the retrosplenial granular cortex and the hippocampus. In the hippocampus, Cbln1 immunoreactivity was present at the molecular layer of the dentate gyrus and the stratum lacunosum-moleculare without overt mRNA expression, suggesting that Cbln1 is provided by perforant path fibers. Retention/retrieval, but not acquisition, of cued and contextual fear memory was impaired in forebrain-predominant Cbln1-null mice. Spatial learning in the radial arm water maze was also abrogated. In contrast, acquisition of fear memory was affected in cerebellum-predominant Cbln1-null mice. These results indicate that Cbln1 in the forebrain and cerebellum mediates specific aspects of fear conditioning and spatial memory differentially and that Cbln1 signaling likely regulates motor and non-motor functions in multiple brain regions.
  
  
  
  Despites its well known role in motor coordination and motor learning, whether and how the cerebellum is involved in cognitive functions remains less clear. Cerebellin 1 (Cbln1) is highly expressed in the cerebellum and serves as an essential synaptic organizer. Although genes encoding Cbln1 and its receptor are associated with many psychiatric disorders, it remains unknown whether such cognitive impairments are caused by cerebellar dysfunction. Here, we show that Cbln1 is also expressed in the forebrain, including the hippocampus and retrosplenial granular cortex. Using forebrain- and cerebellum-predominant conditional Cbln1-null mice, we show that Cbln1 in the forebrain and cerebellum mediates specific aspects of fear conditioning and spatial memory differentially, indicating that Cbln1 signaling regulates both motor and non-motor functions in multiple brain regions.
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.
authors.forename: Shintaro
authors.identifier: 0000-0002-1890-9971
authors.initials: S
authors.lastname: Otsuka
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.|Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan, and.
authors.forename: Kohtarou
authors.initials: K
authors.lastname: Konno
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.|Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Motohashi
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kohda
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.|Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.|Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan, and.
authors.forename: Masahiko
authors.identifier: 0000-0001-5037-7138
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan, myuzaki@a5.keio.jp.|Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.
authors.forename: Michisuke
authors.identifier: 0000-0002-5750-3544
authors.initials: M
authors.lastname: Yuzaki
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000502:physiology*; D003214:Conditioning, Classical / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009044:Motor Cortex / Q000502:physiology; D009068:Movement / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016548:Prosencephalon / Q000502:physiology*; D011498:Protein Precursors / Q000378:metabolism*; D065852:Spatial Memory / Q000502:physiology*
chemical_list: C092370:Cbln1 protein, mouse; D009419:Nerve Tissue Proteins; D011498:Protein Precursors
keywords: cerebellum; fear conditioning; hippocampus; retrosplenial granular cortex; synapse formation