title: Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures.
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.
authors.affiliation: 1] Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan [2].
authors.forename: Naoko H
authors.initials: NH
authors.lastname: Tomioka
authors.affiliation: Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: 1] Laboratory for Neurobiology of Synapse, RIKEN BSI, Wako-shi, Saitama 351-0198, Japan [2] Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyamoto
authors.affiliation: 1] Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan [2] Department of Medical Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Hatayama
authors.affiliation: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Morimura
authors.affiliation: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Laboratory for Neurogenetics, RIKEN BSI, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Odagawa
authors.affiliation: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.
authors.forename: Yuri S
authors.initials: YS
authors.lastname: Odaka
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN BSI, Wako-Shi, Saitama 351-0198, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Ji
authors.initials: J
authors.lastname: Won Um
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
authors.affiliation: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka 420-8688, Japan.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, Hirosaki 036-8216, Japan.
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Pediatrics, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
authors.affiliation: Support Unit for Animal Experiments, RIKEN BSI, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN BSI, Wako-Shi, Saitama 351-0198, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Laboratory for Neurogenetics, RIKEN BSI, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
authors.affiliation: 1] Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan [2] Department of Medical Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Aruga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006801:Humans; D007395:Interneurons / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012640:Seizures / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D009419:Nerve Tissue Proteins; D018094:Receptors, Metabotropic Glutamate; C000602318:ELFN1 protein, human; C576183:extracellular leucine-rich repeat fibronectin containing 1 protein, mouse; C102719:metabotropic glutamate receptor 7