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

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

doi:10.1016/j.isci.2022.104800

Cited by 2 publications

(2 citation statements)

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“…With this status in mind Sato et al prepared a humanized knock-in Vmat1-ki mice via CRISPR/ Cas9-mediated genome editing of VMAT1 to provide additional evidence for the association of specific human variants in this transporter with psychiatric disorders. 132 This humanized mouse included a single human-specific SLC18A1 variant (p.N136I) that is absent in all known mammals, including primates. Characterization of the behavioral, neurophysiological, and molecular changes in the Vmat1-ki compared with wildtype mice, revealed variations in gene expression, enhanced monoamine neurotransmitter uptake into synaptic vesicles, increased monoaminergic signaling and neuronal activity in the amygdala, and a reduction of anxiety-like behaviors.…”

Section: Vesicular Monoamine Transporter (Vmat) Formation And/or Pack...mentioning

confidence: 99%

“…However, despite the proof of functional involvement of VMAT1 in the CNS, 122 and the claimed associations with psychiatric disorders, 123,125 genome‐wide association studies (GWAS) on psychiatric illnesses such as depression 130 and schizophrenia 131 among others, have not detected VMAT1 as a candidate gene. With this status in mind Sato et al prepared a humanized knock‐in Vmat1‐ki mice via CRISPR/Cas9‐mediated genome editing of VMAT1 to provide additional evidence for the association of specific human variants in this transporter with psychiatric disorders 132 . This humanized mouse included a single human‐specific SLC18A1 variant (p.N136I) that is absent in all known mammals, including primates.…”

Section: Vesicular Monoamine Transporter (Vmat) Formation And/or Pack...mentioning

confidence: 99%

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Mouse models for inherited monoamine neurotransmitter disorders

Thöny,

Ng,

Kurian

et al. 2024

J of Inher Metab Disea

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Several mouse models have been developed to study human defects of primary and secondary inherited monoamine neurotransmitter disorders (iMND). As the field continues to expand, current defects in corresponding mouse models include enzymes and a molecular co‐chaperone involved in monoamine synthesis and metabolism (PAH, TH, PITX3, AADC, DBH, MAOA, DNAJC6), tetrahydrobiopterin (BH4) cofactor synthesis and recycling (adGTPCH1/DRD, arGTPCH1, PTPS, SR, DHPR), and vitamin B6 cofactor deficiency (ALDH7A1), as well as defective monoamine neurotransmitter packaging (VMAT1, VMAT2) and reuptake (DAT). No mouse models are available for human DNAJC12 co‐chaperone and PNPO‐B6 deficiencies, disorders associated with recessive variants that result in decreased stability and function of the aromatic amino acid hydroxylases and decreased neurotransmitter synthesis, respectively. More than one mutant mouse is available for some of these defects, which is invaluable as different variant‐specific (knock‐in) models may provide more insights into underlying mechanisms of disorders, while complete gene inactivation (knock‐out) models often have limitations in terms of recapitulating complex human diseases. While these mouse models have common phenotypic traits also observed in patients, reflecting the defective homeostasis of the monoamine neurotransmitter pathways, they also present with disease‐specific manifestations with toxic accumulation or deficiency of specific metabolites related to the specific gene affected. This review provides an overview of the currently available models and may give directions toward selecting existing models or generating new ones to investigate novel pathogenic mechanisms and precision therapies.

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Section: Vesicular Monoamine Transporter (Vmat) Formation And/or Pack...mentioning

confidence: 99%