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

Abstract

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.

Keywords: ACd; BD; BDNF; CREB; CRS; CUS; ECS; ERK; FST; HPA; IES; IL; LH; LTD; LTP; MAOI; MAPK-phosphatase 1; MDD; MKP-1; MRI; MS; N-methyl-d-aspartate glutamate receptor; NMDA; OFC; PS; PTSD; SSRI; antidepressant; bipolar disorder; brain-derived neurotrophic factor; cAMP response element-binding protein; chronic restraint stress; chronic unpredictable stress; dorsal anterior cingulate; electroconvulsive seizure; extracellular-signal-regulated kinase; fMRI; forced swim test; functional magnetic resonance imaging; glutamate; hippocampus; hypothalamic–pituitary–adrenal; inescapable stress; infralimbic; learned helplessness; long-term depression; long-term potentiation; mPFC; mTOR; magnetic resonance imaging; major depressive disorder; mammalian target of rapamycin; maternal separation; medial prefrontal cortex; monoamine oxidase inhibitor; neurotrophic factor; orbitofrontal cortex; posttraumatic stress disorder; prefrontal cortex; prenatal stress; selective serotonin re-uptake inhibitor; stress.

Figure 1. Morphological changes caused by stress

Stress and depression result in opposing effects on spine and dendrite morphology in the PFC, hippocampus and amygdala. In the PFC, as well as hippocampus, chronic stress decreases the number and function of spines, as well as the number and length of dendrite branches of pyramidal neurons. These effects may contribute to the reduced volume of PFC and hippocampus reported in MDD patients. Conversely, chronic stress increases dendrite length and branching in pyramidal neurons in the amygdala. The atrophy of PFC/hippocampus and hypertrophy of amygdala neurons could result in reduction of inhibitory control and increased activity of amygdala, contributing to altered mood, emotion, and anxiety. Antidepressant treatment, particularly new rapid acting NMDA receptor antagonists, can reverse the deficit in synaptic connections in the PFC and thereby reinstate appropriate PFC-amygdala functioning. The effects of antidepressants on stress-induced morphological changes in amygdala have not been determined (indicated by the question mark).

Figure 2. Molecular signaling pathways involved in spine remodeling and neuroplasticity

Shown are the major signaling pathways involved in the regulation of spine remodeling and synaptic plasticity, including NMDA and AMPA glutamate receptor subtypes, neurotrophic factors (i.e., BDNF), and related downstream signaling, particularly the ERK and Akt pathways. Long-term synaptic plasticity and spine formation require protein synthesis, which is regulated in dendrites by activity-dependent activation of the mTOR pathway. Recent studies demonstrate that the rapid synaptogenic and behavioral actions of ketamine are also dependent on mTOR signaling and protein synthesis. Less is known about the mechanisms underlying the atrophy of spines and dendrites in response to stress, but it is possible that inhibition of neurotrophic factor levels, mTOR signaling and synaptic protein synthesis could contribute to the effects of stress. Abbreviations: BDNF, brain-derived neurotrophic factor; TrkB, tropomysin related kinase (BDNF receptor); NMDA, N-methyl-D-aspartate glutamate receptor; AMPA, amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid glutamate receptor; PSD-95; postsynaptic density protein 95; MEK, mitogen activated protein kinase (MAP) kinase kinase; CaMK, calcium-calmodulin-dependent kinase; PI3K, phophotydilinositol-3 kinase; ERK, extracellular-signal-regulated kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin.