Adiponectin as a rapid-acting antidepressant : an investigation of its mechanisms of action

Abstract

The emotional, cognitive, and physiological perturbations caused by major depressive disorder affects millions of people every year, placing it as the leading cause of disability across the world. The delayed therapeutic onset and low remission rates of current antidepressants pose a great challenge for disease treatment. A better understanding of the underlying neuropathology of depression involving the hippocampus and media prefrontal cortex and the discovery of novel rapid-acting antidepressants paved the way for the development of new and more effective pharmacological interventions. Adiponectin is an adipocyte­secreted hormone active in the regulation of the body's energy metabolism and has been suggested as a linking factor between the metabolic state and the brain activity. It modulates the hippocampal structural and functional plasticity, which are two of the main mechanisms involved with the rapid-antidepressant response. Based on that, this research aims to characterize the adiponectin's potential rapid-acting antidepressant effects, investigate whether adiponectin acutely improves hippocampal synaptic and structural plasticity, and determine if the activation of the ventral hippocampus to medial prefrontal cortex (vHipp-mPFC) pathway modulates depression. We showed that, at the 1 h time point, the activation of the adiponectin signaling system is anxiogenic and, when targeting the hippocampus, adiponectin induced an acute depression-like response. Moreover, those effects were paralleled by reduced hippocampal synaptic and structural plasticity in response to acute adiponectin administration. Based on unpublished data in Dr. Yau's Lab and a literature discussion of the sub-chronic effects of serotonergic drugs, these results might implicate adiponectin as a chronic rather than an acute antidepressant. On a parallel experiment, we demonstrated that the activation of the vHipp-mPFC pathway modulates depression-like behavior independent of increased hippocampal proliferation, suggesting this pathway activation might be a separate mechanism implicated in depression relief. In summary, this research increases the understanding of the adiponectin signaling system in mood modulation as well as implicates the vHipp-mPFC pathway as a potential circuit associated with depression relief.