Identifying new clues from how we age
A CAMH discovery of genetic changes that happen during normal aging may provide a new target to treat or prevent depression and other mental illnesses.
In a study published online in August 2016 in Neuropsychopharmacology, CAMH’s Dr. Etienne Sibille and his team showed for the first time in humans how genetic changes in the brain that occur as we age could represent the same sequence of changes occurring in several mental illnesses.
“We learned how a brain mechanism affected by age in a healthy individual is a candidate system for being disrupted by disease,” says Dr. Sibille, Campbell Family Chair in Clinical Neuroscience in CAMH’s Campbell Family Mental Health Research Institute. The important clue could eventually lead to new treatments, a major goal of Dr. Sibille’s research into the links between aging and illness.
(From left) Dr. Hyunjung Oh and Dr. Etienne Sibille
A genetic chain of events
The research team’s focus was a gene called brain-derived neurotropic factor (BDNF), which is important for the healthy functioning of neurons, the nerve cells that form the building blocks of our brain and central nervous system. “Our question was: In the human brain, which role does BDNF have in biological changes that occur with aging, looking specifically at BDNF’s functioning or gene expression?” says Dr. Sibille.
To answer this, the researchers began by examining the post-mortem brains of 209 people ages 16 to 96 years, and nearly 20,000 genes in each person. The first finding was that BDNF’s functioning decreases with age.
Next, the team looked at the relationships between BDNF and the genes that regulate signaling via neurotransmitters, the chemicals that send messages among neurons and to other cells throughout the brain and body. The research confirmed that BDNF is linked with both the brain’s inhibitory or “calming” neurotransmitters, and its excitatory or “stimulating” neurotransmitters. As BDNF function drops, so does the activity of both types of neurotransmitters. GABA, the main inhibitory neurotransmitter, and glutamate, the major excitatory neurotransmitter, are both affected. “Our findings suggest that these changes may contribute to functional impairment of the brain and cognitive decline that occur with aging,” says Dr. Hyunjung Oh, first author of the paper.
Because these changes may have occurred over many years, what was not clear was the chain of events leading to both of these changes. The final clue came from investigating preclinical models at an early stage of reduced BDNF function. “We found that only inhibitory genes were affected, not excitatory,” says Dr. Sibille. “Therefore, this tells us that the potential sequence of events is decreased BDNF, then decreased GABA or inhibition, then there is a compensation with decreased excitatory function. This helps to maintain equilibrium between inhibitory and excitatory functions in the brain.”
New insights into mental illnesses
How do these new findings help us better understand mental illnesses? Earlier research has shown that lower inhibition, or GABA function, is a characteristic of several mental illnesses, including depression, bipolar disorder, schizophrenia, Alzheimer’s disease and Parkinson’s disease. In aging, the change in GABA would occur over a long period, allowing time to adapt, but this change appears to be accelerated in mental illnesses. “We’ve shown in other studies that normal age-related changes in GABA function occur early in depression,” says Dr. Sibille. “These new findings give us insight into the mechanisms that underlie these changes in mental illnesses.”
By pinpointing the sequence of events, “this research confirms that GABA dysfunction is a valid target, because we now know that lower GABA follows BDNF changes, and precedes excitatory changes,” says Dr. Sibille. His long-term goal is to determine if this target could lead to the development of new treatments for mental illnesses.
This research was supported by the National Institute of Mental Health in the U.S.