WASHINGTON: New research using genome editing techniques has allowed scientists to build a model and assess gene mutations associated with neuropsychiatric disorders in humans. Studies have shown how mutations in the brain function and affect anxiety and sociability.
Monoamine neurotransmitters such as serotonin and dopamine play an important role in our cognitive and emotional functions. Their evolutionary origins date back to metazoans, and while the function of related genes is strongly evolutionarily conserved, genetic variation within and between species has been shown to have significant effects on animal mental characteristics such as sociability, aggression, anxiety, and depression.
A research group led by Dr. Dykic sato and professor Masakado Kawata have previously reported that the vesicular monoamine transporter 1 (VMAT1) gene, which transports neurotransmitters to secretory vesicles in neurons and secretory cells, has evolved through natural selection during human evolution. Notably, the 136th amino acid locus of this gene has evolved from Asn to threonine (Thr) in the human lineage, and in addition, a new allele (Isoleucine, Ile) has emerged and its frequencies are increasing worldwide. happened. Previous reports suggested that people with ile Less likely to have depression and anxiety than people with the genotype heart genotype, but it was unclear how these human-specific mutations function in the brain and lead to changes in neuropsychiatric behavior.
In this study, Sato, Kawata (Tohoku University), Yukiko Yu. Inoue (National Center of Neurology and psychiatry), and colleagues created Vmat1 gene-edited mice in which the 136th amino acid locus was replaced with the human genotype (Thr or Ile) via a genome editing technique, and gene expression, neural activity, and behavior varied between genotypes. was compared. Ile-type mice showed decreased levels of anxiety-like behavior, consistent with human studies. Furthermore, genotype affected post-synaptic gene expression and neural activity in the amygdala, a brain region involved in emotional regulation. The functional role of the VMAT1 gene in the central nervous system remains unclear, and this study may provide a step toward elucidating its molecular mechanism. Furthermore, there are few studies in which the effects of single amino acid substitutions under natural selection during human evolution have been verified using genome editing technology. This study demonstrates the functional importance of human-specific forms in regulatory circuits of neurotransmitters involved in cognitive and emotional functions and is expected to shed light on the pathogenic mechanisms of neuropsychiatric disorders such as anxiety and depression.