Sharp minds uncovering the genetics of psychiatric illnesses and brain disorders

Pivotal research from Mount Sinai Hospital points to key genes and early molecular events implicated in common psychiatric illnesses. Specifically, three researchers under the supervision of Dr. John Roder, a senior scientist at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, are uncovering new clues that will help build targeted drug therapies for neurological and psychiatric illnesses including schizophrenia, anxiety, post-traumatic disorder (PTSD) and depression.

One of these researchers is Greer Kirshenbaum, a PhD student who is working to decipher the genetic and molecular mechanisms underlying bipolar disorder, by using animal models of disease. “The current treatments for bipolar disorder leave much to be desired, and the condition is genetically complex,” says Kirshenbaum. “By identifying key genes that may underlie the disorder, we can begin to develop treatments that target the specific cause in a particular patient and thereby help control moods.”

Kirshenbaum is currently exploring a particular gene called NKA, which is implicated in bipolar disorder (specifically in the mania phase). Her team found that reduced NKA activity alters calcium levels, which triggers a cascade of signals in the ERK pathway, known to be linked to bipolar disorder. As a result, the normal pattern of neuronal signaling via neurotransmitters (i.e., brain chemical messengers) is disrupted, altering mood and behaviour.

“This new research follows up on a 50 year-old hypothesis that the NKA gene is involved in bipolar disorder, but this is the first genetic model that has been developed to study its role in mania and bipolar disorder,” explains Kirshenbaum. “What is most notable is that the mouse model can be readily applied to studying the gene’s effects in humans as well.”

While Kirshenbaum focuses on bipolar disorder, Laleh Sinai, another PhD student in Dr. Roder’s lab, is conducting new research into PTSD.  “I became interested in this area because it’s typically understudied and poorly understood,” says Sinai. “I’m fascinated by memories that involve emotions.”

By using animal models of disease, Sinai and her team can get a close-up view of the molecular mechanisms underlying learning and memory, to better understand brain illnesses and psychiatric disorders.

“The process of acquiring and retrieving memories involves a complex cascade of events, including the release and uptake of neurotransmitters at the synapse,” explains Sinai. Memories that reactivate feelings of fear (for example, after a stressful or traumatic experience), trigger the release of certain neurotransmitters in the amygdala—one of the ‘oldest’ parts of the brain that plays a key role in memory and emotions.

By testing with social recognition tasks, Sinai and her team found that the amygdala is altered in psychiatric disorders including anxiety and PTSD.

Sinai employed a compound to block a specific tyrosine kinase (an enzyme involved in triggering signals within the cell) called ‘Src,’ which plays a key role in the fear response and other functions of the amygdala. Blocking this cascade of events can help lessen feelings of fear associated with a traumatic event.

Knowing more about these molecular mechanisms will help Sinai and her team develop new therapeutic targets that can eventually be used to treat people with PTSD or anxiety.

Another key focus in the Roder lab is depression, which affects thousands of Canadians and incurs a significant healthcare burden. To better understand this condition, Research Associate Dr. Tatiana Lipina has honed in on a gene called Disrupted-in-Schizophrenia (also known as DISC1), which is associated with increased risk for depression, as well as schizophrenia and bipolar disorder.

In her current research project, Dr. Lipina has identified genetic factors that regulate the function of DISC1 and lead to depression, as well as uncovered new ways to prevent the gene’s deleterious effects. The results will help researchers and clinicians discover future treatments for these debilitating psychiatric illnesses.

“There is a need to develop better preventative strategies for depression and more effective therapies,” says Dr. Lipina, noting that most current antidepressants have to be given chronically and their efficacies are near 60 per cent at best. “In our studies of DISC1, we identified changes in the nucleus accumbens, a key brain area implicated in the pathology of depression. DISC1 may regulate brain pathways linked to depression, so by finding new approaches to control DISC1 function, we may be better able to prevent and treat depression more effectively.”