Study reveals how mutation functions in the brain, affects anxiety and sociality

Using genome editing technologies, scientists were able to develop a model and examine a gene mutation linked to neuropsychiatric illnesses in humans. The research has demonstrated how the mutation impacts anxiety and sociality in the brain.

Serotonin and dopamine are monoamine neurotransmitters that play crucial roles in our cognitive and emotional functioning. While the function of linked genes is substantially evolutionarily conserved, genetic diversity within and between species has been shown to have a considerable influence on animal mental qualities such as sociality, aggressiveness, anxiety, and depression.

A research group led by Dr Daiki Sato and Professor Masakado Kawata has 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.

In particular, the 136th amino acid locus of this gene has evolved in the human lineage from asparagine (Asn) to threonine (Thr), and moreover, a new allele (isoleucine, Ile) has emerged and increased in its frequencies around the world. Previous reports suggested that people with the Ile genotype are less prone to depression and anxiety than those with the Thr 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 U. Inoue (National Center of Neurology and Psychiatry), and their colleagues prepared Vmat1 gene-edited mice in which the 136th amino acid locus was replaced with the human genotype (Thr or Ile) via genome editing technology, and compared gene expression, neural activity, and behavior among genotypes.

Anxiety-like behaviours were reduced in Ile-type mice, which was similar with human findings. Furthermore, the genotype influenced post-synaptic gene expression as well as neuronal activity in the amygdala, a brain area involved in emotional regulation. The VMAT1 gene’s functional involvement in the central nervous system is unknown, and this work might help to shed light on its molecular underpinnings.

Furthermore, few research have used genome editing technologies to validate the consequences of single amino acid mutations under natural selection during human evolution. This work highlights the functional relevance of human-specific variations in neurotransmitter regulatory circuits involved in cognitive and emotional activities, and it is likely to offer insight on the pathogenic underpinnings of neuropsychiatric illnesses including anxiety and depression.