Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice

Naoko Morimura (), Hiroki Yasuda, Kazuhiko Yamaguchi, Kei-ichi Katayama, Minoru Hatayama, Naoko H. Tomioka, Maya Odagawa, Akiko Kamiya, Yoshimi Iwayama, Motoko Maekawa, Kazuhiko Nakamura, Hideo Matsuzaki, Masatsugu Tsujii, Kazuyuki Yamada, Takeo Yoshikawa and Jun Aruga ()
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Naoko Morimura: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI) Wako
Hiroki Yasuda: Education and Research Support Center, Gunma University Graduate School of Medicine
Kazuhiko Yamaguchi: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI) Wako
Kei-ichi Katayama: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI) Wako
Minoru Hatayama: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI) Wako
Naoko H. Tomioka: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI) Wako
Maya Odagawa: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI) Wako
Akiko Kamiya: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI) Wako
Yoshimi Iwayama: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute (BSI) Wako
Motoko Maekawa: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute (BSI) Wako
Kazuhiko Nakamura: Hirosaki University School of Medicine
Hideo Matsuzaki: Research Center for Child Mental Development, University of Fukui
Masatsugu Tsujii: Faculty of Contemporary Sociology, Chukyo University
Kazuyuki Yamada: Support Unit for Animal Experiments, RIKEN Brain Science Institute (BSI) Wako
Takeo Yoshikawa: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute (BSI) Wako
Jun Aruga: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI) Wako

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract Lrfn2/SALM1 is a PSD-95-interacting synapse adhesion molecule, and human LRFN2 is associated with learning disabilities. However its role in higher brain function and underlying mechanisms remain unknown. Here, we show that Lrfn2 knockout mice exhibit autism-like behavioural abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits, together with enhanced learning and memory. In the hippocampus, the levels of synaptic PSD-95 and GluA1 are decreased. The synapses are structurally and functionally immature with spindle shaped spines, smaller postsynaptic densities, reduced AMPA/NMDA ratio, and enhanced LTP. In vitro experiments reveal that synaptic surface expression of AMPAR depends on the direct interaction between Lrfn2 and PSD-95. Furthermore, we detect functionally defective LRFN2 missense mutations in autism and schizophrenia patients. Together, these findings indicate that Lrfn2/LRFN2 serve as core components of excitatory synapse maturation and maintenance, and their dysfunction causes immature/silent synapses with pathophysiological state.

Date: 2017
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DOI: 10.1038/ncomms15800

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