Humanized substitutions of Vmat1 in mice alter amygdala-dependent behaviors associated with the evolution of anxiety

Daiki X. Sato, Yukiko U. Inoue, Nahoko Kuga, Satoko Hattori, Kensaku Nomoto, Yuki Morimoto, Giovanni Sala, Hideo Hagihara, Takefumi Kikusui, Takuya Sasaki, Yuji Ikegaya, Tsuyoshi Miyakawa, Takayoshi Inoue, Masakado Kawata

Research output: Contribution to journalArticlepeer-review


The human vesicular monoamine transporter 1 (VMAT1) harbors unique substitutions (Asn136Thr/Ile) that affect monoamine uptake into synaptic vesicles. These substitutions are absent in all known mammals, suggesting their contributions to distinct aspects of human behavior modulated by monoaminergic transmissions, such as emotion and cognition. To directly test the impact of these human-specific mutations, we introduced the humanized residues into mouse Vmat1 via CRISPR/Cas9-mediated genome editing and examined changes at the behavioral, neurophysiological, and molecular levels. Behavioral tests revealed reduced anxiety-related traits of Vmat1Ile mice, consistent with human studies, and electrophysiological recordings showed altered oscillatory activity in the amygdala under anxiogenic conditions. Transcriptome analyses further identified changes in gene expressions in the amygdala involved in neurodevelopment and emotional regulation, which may corroborate the observed phenotypes. This knock-in mouse model hence provides compelling evidence that the mutations affecting monoaminergic signaling and amygdala circuits have contributed to the evolution of human socio-emotional behaviors.

Original languageEnglish
Article number104800
Issue number8
Publication statusPublished - 19-08-2022

All Science Journal Classification (ASJC) codes

  • General


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