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.

Keywords: Antidepressant; Glutamate; Ketamine; Neurotrophic factor; Stress.

Figure 1

Chronic stress causes atrophy of layer V pyramidal neurons in the medial PFC. Shown is the influence of repeated restraint stress (30 min per day for 7 d) on layer V pyramidal neurons in the medial PFC. The upper panels demonstrate that effects of stress on the length and branching of apical dendrites, and the lower panels show the effects of stress on the density of spines on apical dendrites of labeled layer V neurons. Neurobiotin labeled neurons were visualized by two-photon laser scanning miscrocopy (see Liu and Aghajanian, 2008).

Figure 2

Schematic of the effects of stress/depression on spine synapses and reversal by rapid acting antidepressants. Under normal/nonstressed conditions spine synapse connections are intact and provide control over mood, emotion, and cognition. Chronic stress or depression leads to decreased levels of BDNF and downstream mTORC1 signaling, which contributes to decreased number and function of spine synapses in layer V pyramidal neurons of the medial PFC. Rapid acting antidepressant such as ketamine rapidly reverse the spine synapse deficits caused by stress via a burst of glutamate, which is thought to result from disinhibition of GABAergic interneurons that control glutamate transmission. This increase in glutamate-AMPA leads to activity dependent release of BDNF-TrkB and stimulation of mTORC1 signaling, resulting in increased synthesis of synaptic proteins required for new spine formation. The antidepressant response to a single dose of ketamine persists for approximately 7 day in humans and rodents before relapse. The new spines induced by ketamine also remain for a similar length of time, and the loss of spines could be related to relapse and reversal of antidepressant responses.