The involvement of synaptic degeneration in major depressive disorder and antidepressant mechanism of action

Abstract

Major Depressive Disorder (MDD) is a neuropsychiatric syndrome where patients exhibit symptoms of low mood, anhedonia, and cognitive impairment. Studies have shown an intimate relationship between the effects of stress and the pathophysiology of depression. Elevated cortisol levels resulting from disturbance of the hypothalamus-pituitary-adrenal axis has been observed in depressed patients. Studies have also shown that the hippocampus is severely affected in depression. Although studies have provided evidence on the pathophysiology of depression, the precise mechanisms remain to be elucidated. Increasing lines of evidence have demonstrated synaptic changes in mood disorders, including depression. We hypothesize that progressive synaptic degeneration may initiate pathological changes in healthy neurons and antidepressants can function as a neuroprotective agent. In the present study, we used primary cultures of hippocampal neurons as an experimental model and neurons exposed to corticosterone as an in vitro model for depression. To simulate depression, we used a sub-lethal dosage of corticosterone over a long time point of 48 hours. Immunocytochemical analysis of synaptic and cytoskeletal proteins were used to investigate effects of cortisosterone. Results showed aggregations of the presynaptic proteins, synaptotagmin, and synaptophysin. Microtubule associated protein 2 (MAP2) staining of the dendrites revealed dendritic varicosities. Increased staining of phosphorylated neurofilaments (SMI-312) was also observed. Pre-treatment with imipramine and escitalopram (20 μM for both) were able to alleviate the detrimental effects. These results suggest the involvement of synaptic degeneration in corticosterone-induced toxicity and the ability of antidepressants to alleviate the observed pathology. Hence, synaptic degeneration could contribute to the pathophysiology of depression and antidepressants could be exerting its effects through synapse protection. Further studies to elucidate the synapse-related neuroprotective mechanisms of antidepressants are planned.