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

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  • Aruga Jun
    Department of Medical Pharmacology, Nagasaki University Institute of Biomedical Sciences, Japan Laboratory for Behavioral and Developmental Disorders, RIKEN BSI, Japan
  • Morimura Naoko
    Laboratory for Behavioral and Developmental Disorders, RIKEN BSI, Japan
  • Yasuda Hiroki
    Gunma University Graduate School of Medicine, Japan
  • Katayama Kei-ichi
    Laboratory for Behavioral and Developmental Disorders, RIKEN BSI, Japan
  • Hatayama Minoru
    Department of Medical Pharmacology, Nagasaki University Institute of Biomedical Sciences, Japan Laboratory for Behavioral and Developmental Disorders, RIKEN BSI, Japan
  • Yoshikawa Takeo
    Laboratory for Molecular Psychiatry, RIKEN BSI, Japan

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<p>Excitatory synapses have a fundamental role for maintenance of normal brain function, and dysfunctions of the synaptic molecules lead to several neuropsychiatric disorders. Lrfn2/SALM1, a PSD-95-interacting synapse adhesion molecule, is implicated as a causative gene for learning disabilities (LDs) and antisocial personal disorders (ASPD). However, its role in higher brain function and underlying mechanisms remain unknown. Here we show that Lrfn2 knockout mice exhibited autism-like behavioral abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities, and prepulse inhibition deficits, together with enhanced learning and memory. In the KO hippocampus, the protein levels of PSD-95 and synaptic GluA1 were decreased whereas GluN2A was increased, and the LTP was enhanced with reduction of AMPA/NMDA ratio, suggesting that Lrfn2 impacts on synaptic localization of glutamate receptors. We also detected functionally defective LRFN2 missense mutations in autism and schizophrenia patients. These findings indicate that Lrfn2/LRFN2 is required for proper synaptic expression of glutamatergic signal components and their dysfunction causes immature synapses with pathophysiological state.</p>

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