2025年 新着論文 28 病態シグナル学分野から論文が発表されました

Necl-4/CADM4 regulates GABAergic synaptic strength on GABAergic inhibitory neurons via ErbB4 activation and prevents neuronal impairments

Mol Neurobiol. 2025 Jul 29. doi: 10.1007/s12035-025-05230-8. Online ahead of print.

Authors

Ryouhei Komaki  1   2 Hajime Shiotani  1   3 Toshihiko Kuriu  4   5 Takeshi Kameyama  1 Muneaki Miyata  1   3 Shin Kedashiro  1   3 Kimitaka Katanazaka  1   2 Shota Nishii  1   2 Norio Chihara  2 Riki Matsumoto  2   6 Michinori Koebis  7 Atsu Aiba  7 Kiyohito Mizutani  8   9 Yoshimi Takai  10

Affiliations

  • 1 Division of Pathogenetic Signaling, Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0047, Japan.
  • 2 Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan.
  • 3 Division of Pathogenetic Signaling, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Tokushima, 770-8503, Japan.
  • 4 Center for Medical Research and Development, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-8686, Japan.
  • 5 Clinical Research Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Osaka, 569-8686, Japan.
  • 6 Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, 606-8507, Japan.
  • 7 Section of Animal Research and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
  • 8 Division of Pathogenetic Signaling, Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0047, Japan. kiyohito_mizutani@tokushima-u.ac.jp.
  • 9 Division of Pathogenetic Signaling, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Tokushima, 770-8503, Japan. kiyohito_mizutani@tokushima-u.ac.jp.
  • 10 Division of Pathogenetic Signaling, Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0047, Japan. ytakai@med.kobe-u.ac.jp.

Abstract

Neural networks comprise excitatory and inhibitory neurons, linked through excitatory and inhibitory synapses. Synaptic excitation/inhibition balance is controlled for brain development and functions, and its dysregulations are implicated in aging-dependent neuronal impairments. Here, we found that Necl-4/CADM4, an immunoglobulin superfamily cell adhesion molecule, is expressed in γ-aminobutyric acidergic (GABAergic) inhibitory neurons and localizes at GABAergic synapses on inhibitory neurons in cultured hippocampal neurons and the mouse hippocampus. Necl-4 genetic ablation induced neuronal loss with synaptic degenerations in the hippocampus, and cultured Necl-4-knockout (KO) hippocampal neurons were more susceptible to death. Prior to the neuronal death, the Necl-4-KO hippocampal neurons showed an increase in GABAergic synapse density on inhibitory neurons and in synaptic molecules at GABAergic synapses on inhibitory neurons, which were regulated by ErbB4 activation. Furthermore, electrophysiological analysis revealed that Necl-4 genetic ablation enhanced GABAergic synaptic currents on inhibitory neurons and induced high-frequency firing in dissociated hippocampal cultures composed of glutamatergic excitatory neurons and inhibitory neurons, contributing to excitotoxicity-mediated neuronal death. Thus, Necl-4 regulates GABAergic synaptic strength on inhibitory neurons via ErbB4 activation and prevents neuronal impairments.

Keywords: ErbB4; GABA receptor; GABAergic synapses; Inhibitory neuron; Necl-4/CADM4; Neuronal impairments.

Conflict of interest statement

Declarations. Ethics Approval: All animal experiments were performed in accordance with institutional guidelines and approved by the administrative panel on laboratory animal care of Kobe University. This study was approved by the president of Kobe University after being reviewed by the Kobe University Animal Care and Use Committee (approval No. 30–06-01, 30–07-01, and P230506), and animal experiments were conducted in accordance with regulations for animal experimentation of Kobe University. Competing Interests: Michinori Koebis is currently employed at Eisai Co. All the other authors declare that they have no competing interests.

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