Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures

Naoko H. Tomioka, Hiroki Yasuda, Hiroyuki Miyamoto, Minoru Hatayama, Naoko Morimura, Yoshifumi Matsumoto, Toshimitsu Suzuki, Maya Odagawa, Yuri S. Odaka, Yoshimi Iwayama, Ji Won Um, Jaewon Ko, Yushi Inoue, Sunao Kaneko, Shinichi Hirose, Kazuyuki Yamada, Takeo Yoshikawa, Kazuhiro Yamakawa and Jun Aruga ()
Additional contact information
Naoko H. Tomioka: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi
Hiroki Yasuda: Education and Research Support Center, Gunma University Graduate School of Medicine
Hiroyuki Miyamoto: Laboratory for Neurobiology of Synapse, RIKEN BSI, Wako-shi
Minoru Hatayama: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi
Naoko Morimura: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi
Yoshifumi Matsumoto: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi
Toshimitsu Suzuki: Laboratory for Neurogenetics, RIKEN BSI, Wako-shi
Maya Odagawa: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi
Yuri S. Odaka: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi
Yoshimi Iwayama: Laboratory for Molecular Psychiatry, RIKEN BSI, Wako-Shi
Ji Won Um: College of Life Science and Biotechnology, Yonsei University
Jaewon Ko: College of Life Science and Biotechnology, Yonsei University
Yushi Inoue: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders
Sunao Kaneko: Hirosaki University Graduate School of Medicine
Shinichi Hirose: Fukuoka University School of Medicine
Kazuyuki Yamada: Support Unit for Animal Experiments, RIKEN BSI, Wako-shi
Takeo Yoshikawa: Laboratory for Molecular Psychiatry, RIKEN BSI, Wako-Shi
Kazuhiro Yamakawa: Laboratory for Neurogenetics, RIKEN BSI, Wako-shi
Jun Aruga: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: Abstract GABAergic interneurons are highly heterogeneous, and much is unknown about the specification and functional roles of their neural circuits. Here we show that a transinteraction of Elfn1 and mGluR7 controls targeted interneuron synapse development and that loss of Elfn1 results in hyperactivity and sensory-triggered epileptic seizures in mice. Elfn1 protein increases during postnatal development and localizes to postsynaptic sites of somatostatin-containing interneurons (SOM-INs) in the hippocampal CA1 stratum oriens and dentate gyrus (DG) hilus. Elfn1 knockout (KO) mice have deficits in mGluR7 recruitment to synaptic sites on SOM-INs, and presynaptic plasticity is impaired at these synapses. In patients with epilepsy and attention deficit hyperactivity disorder (ADHD), we find damaging missense mutations of ELFN1 that are clustered in the carboxy-terminal region required for mGluR7 recruitment. These results reveal a novel mechanism for interneuron subtype-specific neural circuit establishment and define a common basis bridging neurological disorders.

Date: 2014
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DOI: 10.1038/ncomms5501

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