Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you give a brief introduction to adult neurogenesis? How is this process important for depression and electroconvulsive therapy?
There are two regions in the brain that continue to produce new neurons well into adulthood. One of these regions is the hippocampus and as we converse this region is actively involved in memory formation, mood regulation and cognition.
Neurons are produced from neural stem cells in the dentate gyrus of the hippocampus, and this entire process is regulated by both internal factors and external influences.
In recent times, the community including us has found treatments such as electroconvulsive therapy and antidepressants proceed by stimulating adult-generated neural stem cells in the dentate gyrus of hippocampus, enhancing their developmental process and increasing the production of new neurons. Indeed, these effects play an essential role in achieving antidepressant efficacy.
How did your research into adult neurogenesis and these therapies begin?
My interest really began during graduate school when I studied the effects of antidepressants on adult neurogenesis in prenatally stressed offspring rats in Dr. Changju Kim’s laboratory at Kyunghee University in South Korea.
During my post-doctoral work in Dr. Hongjun Song’s laboratory at Johns Hopkins, I became more interested in the molecular and cellular mechanisms underlying this process. Studying the effects and mechanisms of antidepressant therapy was a natural extension of my work in understanding the functional role of adult neurogenesis.
What did your research involve?
In general, my research has involved understanding adult hippocampal neurogenesis both from a cellular/molecular and behavioural/functional perspective. This is usually accomplished through techniques in molecular biology, animal genetics, behavioural neuroscience and high-resolution confocal imaging.
My recent work on sFRP3, adult neurogenesis and antidepressants utilized technologies such as lentiviruses and adenoretroviruses to knockdown specific gene expression, in vivo clonal analysis (developed in Dr. Hongjun Song’s lab at Johns Hopkins) to sparsely label radial-glia like neural stem cells and human pharmacogenetic association analysis (conducted by Dr. Elisabeth Binder at Emory University).
Why did you carry out your research in mice?
Mice afford us a very flexible model in which to conduct experiments which cannot be done in humans without invasive procedures. They are a powerful model in which to manipulate genetics and produce mutant strains.
Many neuropsychiatric disorders are complex and require interaction between various cellular and molecular niches. It is difficult to study these in in vitro culture since the conditions do not replicate the complex niches or signaling that occur between different cell types and molecules in an organism.
Mice provide us a powerful model where we can knock down or over-express genes in specific cell types and analyse resulting changes in the neuronal population and circuitry. We previously took advantage of a combination of behavioral and genetic studies in mice to study the effect of antidepressants and decipher the basic mechanisms of neuropsychiatric etiology. We will continue to take similar approaches in the future.
What did your research find?
Our recent research shows that antidepressant action is mediated through their action on a key player that regulates neural stem cell activation and consequent maturation.
sFRP3 is this key protein, the expression of which is decreased by increased neuronal activity and suppressed during antidepressant treatment. In this activity-dependent manner, it not only regulates adult neurogenesis but also mediates the final behavioral or cognitive response from antidepressant treatment.
Do you think your results would be applicable to humans?
Yes, we believe so. As I mentioned, sFRP3 mediates antidepressant action in mice. We followed this work by conducting a human pharmacogenetic association analysis.
We found that polymorphisms in FRZB (the human sFRP3 gene) contribute to a better response in clinical cohorts, potentially via differential regulation of FRZB expression in the human brain.
Do you think this research will allow more personalized depression treatments in the future?
Yes, it’s a hopeful step in that direction. sFRP3 is a molecule that links antidepressant treatment to neural stem cell activation. This can allow us to fine-tune depression therapy for individuals or predict their response accordingly.
There is also ample evidence linking adult hippocampal neurogenesis to other psychiatric disorders. Harnessing such knowledge can allow development of more personalized therapeutic strategies for other disorders as well.
How do you think the future of depression therapy will develop?
Treatments such as electroconvulsive therapy and antidepressants have proven useful and will continue to be utilized alongside better diagnostic tools and emerging treatments such as deep brain stimulation.
The scientific community has also found many susceptibility genes important in psychiatric disorders. To that end, individualized depression therapy based on one’s genetic make-up will also develop and prove powerful.
Where can readers find more information?
PubMed is a great source to obtain information on the subject. My recently published work can also be found on the Molecular Psychiatry and Stem Cell journal websites.
Secreted frizzled-related protein 3 (sFRP3) regulates antidepressant responses in mice and humans
Cell Stem Cell:
Secreted Frizzled-Related Protein 3 regulates activity-dependent adult hippocampal neurogenesis
About Mi-Hyeon Jang
Since 2012, Dr. Mi-Hyeon Jang has been an assistant professor in the Department of Neurologic Surgery at the Mayo Clinic in Rochester, Minnesota.
Currently, her team is focusing on determining the molecular targets involved in regulation of adult hippocampal neurogenesis and related behavioral responses altered in mental disorders.
Her team includes Heechul Jun, Syed M.Q. Hussaini, Chang Hoon Cho, Hyo Jin Kim.
Their end goal is to harness the regenerative capacity of new born neurons toward an optimal clinical outcome and improved treatment options for brain disorders.