Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression

Dendritic spines provide a compartment for assembly and functional organization of synaptic machinery that plays a fundamental role in neuronal communication and neuroplasticity. Studies in humans as well as in animal models have demonstrated abnormal spine architecture in several psychiatric disorders, including depression and other stress-related illnesses. The negative impact of stress on the density and organization of spines is thought to contribute to the behavioral deficits caused by stress exposure. Moreover, there is now evidence that medication-induced recovery involves changes in synaptic plasticity and dendrite morphology, including increased expression of pre- and postsynaptic plasticity-related proteins, as well as the density and function of axo-spinous synapses. Here we review the evidence from brain imaging and postmortem studies demonstrating that depression is accompanied by structural and functional alterations of cortical and limbic brain regions, including the prefrontal cortex, hippocampus and amygdala. In addition, we present more direct evidence from basic research studies that exposure to stress alters spine morphology, function and plasticity and that antidepressants, particularly new rapid acting agents, reverse these effects. Elucidation of the signaling pathways and molecular mechanisms that control spine synapse assembly and plasticity will contribute to a better understanding of the pathophysiology of depression and development of novel, more effective therapeutic agents.