SYNAPTIC PLASTICITY IN DEPRESSION

Depression is a devastating illness that is rapidly becoming the second largest cause of disability worldwide. Clinical management of this disease is limited due to the delayed onset of antidepressant action and the high rate of resistance (~70%) against first line medications. The main reason of these difficulties is the incomplete understanding of depression neurobiology. There are many hypotheses of depression, such as the monoamine hypothesis, upon which the mechanisms of most currently available antidepressant treatments are based. These theories are repeatedly challenged in the forefront of depression research, and even the better of them are considered inadequate in comprehensively explaining depression neurobiology and antidepressant response.

In the last few years, Dr. Hajszan’s research at Yale University in the United States has provided evidence that remodeling of hippocampal and prefrontal spine synapses plays a critical role in depression neurobiology, both in laboratory animals and in human subjects. Specifically, the less synapses the subjects have, the more depressed they become. The most convincing confirmation of our “synaptogenic hypothesis” came from studies reporting that the rapid antidepressant response to ketamine is based on fast synaptic activation in the prefrontal cortex.

Building upon the synaptogenic hypothesis, we have identified an antidepressant candidate molecule that reverses depressive behavior via increasing the number of hippocampal spine synapses in a matter of minutes. For conventional monoaminergic antidepressants, such as desipramine or fluoxetine, it takes days or weeks to exert similar effects in various animal models of depression. While its rigorous preclinical testing continues in our laboratory, translational research to further develop this antidepressant candidate for use in human therapy is carried out by our partner biotechnology and pharmaceutical companies. Our goal is to develop the first antidepressant that is capable of providing rapid relief from depressive symptoms in nonclinical settings.

Work in our laboratory also addresses antidepressant resistance, the other critical problem of depression neurobiology. Similar to the challenge of identifying a rapidly acting antidepressant, we firmly believe that antidepressant resistance could also be solved by applying our understanding of how spine synapses respond to stress, depression, and antidepressant treatment. We hypothesize that antidepressant resistance is caused by factors that interfere with the synaptogenic effect of antidepressants, such as continued stress, neuroinflammation, derailed energy metabolism, lack of neurotrophic support, and/or genetic abnormalities. One of our main goals currently is to improve antidepressant response by protecting synapses from the devastating effects of stress.

To investigate the neurobiology of depression, we use a wide selection of state of the art neuroscience methods, including a battery of animal (mostly rodent) behavioral models of depression, stress, anxiety, and cognition, as well as electrophysiology, electron microscopic stereology, and various genomic and proteomic approaches. Our laboratory is in the forefront of preclinical research on depression, with our results being published in leading journals of the field.