Deletion of the vesicular monoamine transporter 1 (vmat1/slc18a1) gene affects dopamine signaling

Lohoff, Falk W.; Carr, Gregory V.; Brookshire, Bethany R.; Ferraro, Thomas N.; Lucki, Irwin

doi:10.1016/j.brainres.2019.01.029

Cited by 8 publications

(14 citation statements)

References 43 publications

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“…Genetic changes in VMAT1 could thus affect the amount of monoamines contained in vesicles, which is in turn released from the nerve terminal, affecting downstream signaling. A recent study has shown that VMAT1 knockout in mice lead to differential dopamine signaling [52], and several other studies have revealed the association of the 136Thr with a variety of psychiatric phenotypes including alcohol dependence [38, 53], bipolar disorders [34], autism [39], anxiety [37, 38], maladaptive impulsivity, depressiveness, and neuroticism [38]. A functional neuroimaging study has revealed that this variant has distinct influences on activity of the prefrontal cortex and amygdala [44], both of which play crucial roles in emotional processing, that may underlie the socioemotional differences observed in the abovementioned studies.…”

Section: Discussionmentioning

confidence: 99%

Human-specific mutations in VMAT1 confer functional changes and multi-directional evolution in the regulation of monoamine circuits

et al. 2019

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BackgroundNeurochemicals like serotonin and dopamine play crucial roles in human cognitive and emotional functions. Vesicular monoamine transporter 1 (VMAT1) transports monoamine neurotransmitters, and its variant (136Thr) is associated with various psychopathological symptoms and reduced monoamine uptake relative to 136Ile. We previously showed that two human-specific amino acid substitutions (Glu130Gly and Asn136Thr/Ile) of VMAT1 were subject to positive natural selection. However, the potential functional alterations caused by these substitutions (Glu130Gly and Asn136Thr) remain unclear. To assess functional changes in VMAT1 from an evolutionary perspective, we reconstructed ancestral residues and examined the role of these substitutions in monoamine uptake in vitro using fluorescent false neurotransmitters (FFN), which are newly developed substances used to quantitatively assay VMATs.ResultsImmunoblotting confirmed that all the transfected YFP-VMAT1 variants are properly expressed in HEK293T cells at comparable levels, and no significant difference was seen in the density and the size of vesicles among them. Our fluorescent assays revealed a significant difference in FFN206 uptake among VMAT1 variants: 130Glu/136Asn, 130Glu/136Thr, and 130Gly/136Ile showed significantly higher levels of FFN206 uptake than 130Gly/136Asn and 130Gly/136Thr, indicating that both 130Glu and 136Ile led to increased neurotransmitter uptake, for which 136Thr and 136Asn were comparable by contrast.ConclusionsThese findings suggest that monoamine uptake by VMAT1 initially declined (from 130Glu/136Asn to 130Gly/136Thr) in human evolution, possibly resulting in higher susceptibility to the external environment of our ancestors.

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Section: Discussionmentioning

confidence: 99%

Human-specific mutations in VMAT1 confer functional changes and multi-directional evolution in the regulation of monoamine circuits

et al. 2019

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“…4d). Lohoff et al reported that Vmat1 KO affected DA signaling in particular, with upregulation of D2R and downregulation of tyrosine hydroxylase (TH) observed in both the frontal cortex and striatum (32). Given the association between Vmat1 KO and decreased DA in the frontal cortex, we speculated that Vmat1 Ile/Ile mice would also exhibit downregulation of D2R and upregulation of TH compared to WT mice.…”

Section: Phenotypic Changes In Mice Caused By the Humanized Vmat1mentioning

confidence: 90%

“…These genes include many involved in adrenergic (Adra2b), dopaminergic (Adcy5, Adora2a, Drd1, Drd2, Gnal, Gng7, Gpr6, Gpr88, Pde1b, Pde1c, Pde7b, Pde10a, Pdyn, Penk, Ppp1r1b, Rasgrp2, Rgs9 and Tac1), glutamatergic (Grm4), and serotonergic (Htr1b, Htr1d, Htr1f, and Htr4) signaling pathways. Lohoff et al reported that Vmat1 KO affected DA signaling in particular, with upregulation of D2R and downregulation of tyrosine hydroxylase (TH) observed in both the frontal cortex and striatum 24 . Given the association between Vmat1 KO and decreased DA in the frontal cortex, we speculated that Vmat1 Ile/Ile mice would also exhibit downregulation of D2R and upregulation of TH compared to WT mice.…”

Section: Differential Regulation Of Dopaminergic and Neurodevelopmental Genes In The Amygdala By Vmat1 Genotypementioning

confidence: 99%

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

Sato

Inoue

Morimoto

et al. 2021

Preprint

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The human vesicular monoamine transporter 1 (VMAT1) harbors unique substitutions (Asn136Thr/Ile) that alter 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 transmission, 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 amygdala-specific changes in the expression of genes 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.

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“…Lohoff et al. reported that Vmat1 KO affected DA signaling in particular, with upregulation of D2R and downregulation of tyrosine hydroxylase (TH) observed in both the frontal cortex and striatum ( Lohoff et al., 2019 ). Given the association between Vmat1 KO and decreased DA in the frontal cortex, we speculated that Vmat1 Ile/Ile mice would also exhibit downregulation of D2R and upregulation of TH compared with WT mice.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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Deletion of the vesicular monoamine transporter 1 (vmat1/slc18a1) gene affects dopamine signaling

Cited by 8 publications

References 43 publications

Human-specific mutations in VMAT1 confer functional changes and multi-directional evolution in the regulation of monoamine circuits

Human-specific mutations in VMAT1 confer functional changes and multi-directional evolution in the regulation of monoamine circuits

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

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

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