Spine synapse remodeling in the pathophysiology and treatment of depression

Abstract

Clinical brain imaging and postmortem studies provide evidence of structural and functional abnormalities of key limbic and cortical structures in depressed patients, suggesting that spine synapse connectivity is altered in depression. Characterization of the cellular determinants underlying these changes in patients are limited, but studies in rodent models demonstrate alterations of dendrite complexity and spine density and function that could contribute to the morphological and functional alterations observed in humans. Rodent studies demonstrate region specific effects in chronic stress models of depression, including reductions in dendrite complexity and spine density in the hippocampus and prefrontal cortex (PFC) but increases in the basolateral amygdala and nucleus accumbens. Alterations of spine synapse connectivity in these regions are thought to contribute to the behavioral symptoms of depression, including disruption of cognition, mood, emotion, motivation, and reward. Studies of the mechanisms underlying these effects demonstrate a role for altered brain derived neurotrophic factor (BDNF) signaling that regulates synaptic protein synthesis. In contrast, there is evidence that chronic antidepressant treatment can block or reverse the spine synapse alterations caused by stress. Notably, the new fast acting antidepressant ketamine, which produces rapid therapeutic actions in treatment resistant MDD patients, rapidly increases spine synapse number in the PFC of rodents and reverses the effects of chronic stress. The rapid synaptic and behavioral actions of ketamine occur via increased BDNF regulation of synaptic protein synthesis. Together these studies provide evidence for a neurotophic and synaptogenic hypothesis of depression and treatment response and indicate that spine synapse connectivity in key cortical and limbic brain regions is critical for control of mood and emotion.

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

“…Although the mechanisms which link stress and alterations of neurotrophic factors' levels are not completely understood, several studies show that antidepressant treatment corrects neurotrophins levels and that normal BDNF signaling is necessary for antidepressant action (Castren et al 2007;Adachi et al 2008). This suggests that these factors play an important role in restoring the physiological function of networks involved in mood disorders (Duman and Duman 2015).…”

New targets for rapid antidepressant action

“…Improved neuronal plasticity (e.g. synaptogenesis, neurogenesis, dendritic remodeling, etc) appears to be a target for ketamine, and may reverse the deleterious effects of long-term depression such as reduced cellular resilience and stress in the hippocampus and PFC (Duman and Duman, 2015). …”

Pharmacological Activation Gi/o Protein Increases Glial Cell Line-Derived Neurotrophic Factor Production through Fibroblast Growth Factor Receptor and Extracellular Signal-Regulated Kinase Pathway in Primary Cultured Rat Cortical Astrocytes

“…35) GDNF and BDNF signaling regulate synaptic protein synthesis and synapse formation. 36,37) Thus, the biological effects of mastoparan-7 could be mediated by increases in endogenous GDNF and BDNF production following Gi/o protein signaling activation. Decreased synaptic efficacy and impaired neural functioning have been suggested as underlying causes of neuropsychiatric and neurodegenerative disorders.…”