Enzyme Mutation May Cause Bipolar Disorder, ADHD, Suicidality

New research suggests psychiatric diseases that affect a patient’s ability to appropriately respond to stimuli may be triggered by the misplacement of an enzyme in the pathway within neurons, according to a study published by Proceedings of the National Academy of Science. These inappropriate responses include the high and low intensity feelings experienced with bipolar disorder, the impulsiveness associated with attention deficit hyperactive disorder (ADHD), and the overwhelming desire to harm oneself in patients who are suicidal, according to the study authors.

Researchers examined neurons that are involved in sending specialized nerve impulses to the area of the brain stem responsible for reacting to stimuli, the medullary reticular nucleus gigantocelluraris (NGC). The researchers identified the neural pathways, known as messenger ribonucleic acid (mRNA), of these nerve impulses.

Researchers noted the presence of an unusual enzyme in the mRNA: endothelial nitric oxide synthase (eNOS), which is typically only found in blood vessels. Two experiments were conducted on mice to examine the association between the out-of-place eNOS in the NGC cells and inappropriate reactionary behavior.

"Discovering that eNOS was in neurons was quite unexpected, and led to further studying when and how the eNOS within neurons is activated, and how such activation manifests in the body," said senior researcher Joel N.H. Stern, PhD.

The first experiment sought to determine when eNOS is most active. The enzymes natural production of nitric oxide enabled researchers to measure its activity level by monitoring oxidation in the cells, according to the study.

While eNOS was not particularly active when the mice were in familiar environments, such as their home cage, the researchers found that eNOS significantly increased during and after exposure to new environments.

In the second experiment, researchers tested how the mice would respond if eNOS in NGC brain cells was inhibited. A chemical that keeps eNOS from functioning by inhibiting the production of nitric oxide was microinfused into the mice’s NGC cells, according to the study.

Mice who had both active and inactive eNOS in their NGC brain cells were exposed to different environments, including one where they could roam freely. The mice with inactive eNOS displayed hyperactive behavior long after they were removed from the stimuli, and returned to their cages.

"A human analogy might be when a person gets excited by something good that happens and cannot come down from that high, or alternatively, gets stuck in a depressive state after a negative experience,” Dr. Stern said.

Previous studies have determined that eNOS gene mutations (NOS-III) may play a role in the inappropriate reactions to stimuli seen in bipolar disorder, and major depressive disorder, according to the researchers. This study suggests that NOS-III mutations may be involved in the development of psychiatric diseases such as bipolar disorder, depression and suicidality, and ADHD. These findings imply that the symptoms of these psychiatric diseases may be treated by adjusting the nitric oxide production in patients with psychiatric diseases.

"The discovery of the presence of eNOS in NGC brain cells, and the effect of eNOS on the length of reactions to stimuli, may signal a new understanding and the discovery of a new mechanism for how certain psychiatric diseases that involve a mutation of the NOS-III gene can potentially be treated or controlled," said Dr. Stern.

Reference

Feinstein Institute researcher uncovers new understanding of certain psychiatric diseases [news release]. Manhasset, NY: July 2, 2018; The Feinstein Institute for Medical Research. http://www.pharmacytimes.com/link/193. Accessed July 5, 2018.