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Review
. 2013 Sep:57:28-37.
doi: 10.1016/j.nbd.2012.05.022. Epub 2012 Jun 9.

Environmental and pharmacological modulations of cellular plasticity: role in the pathophysiology and treatment of depression

Kristie T Ota  1 , Ronald S Duman
Affiliations
Review

Environmental and pharmacological modulations of cellular plasticity: role in the pathophysiology and treatment of depression

Kristie T Ota et al. Neurobiol Dis. 2013 Sep.

Abstract

Atrophy of neurons and gross structural alterations of limbic brain regions, including the prefrontal cortex (PFC) and hippocampus, have been reported in brain imaging and postmortem studies of depressed patients. Preclinical findings have suggested that prolonged negative stress can induce changes comparable to those seen in major depressive disorder (MDD), through dendritic retraction and decreased spine density in PFC and hippocampal CA3 pyramidal neurons. Interestingly, recent studies have suggested that environmental and pharmacological manipulations, including antidepressant medication, exercise, and diet, can block or even reverse many of the molecular changes induced by stress, providing a clear link between these factors and susceptibility to MDD. In this review, we will discuss the environmental and pharmacological factors, as well as the contribution of genetic polymorphisms, involved in the regulation of neuronal morphology and plasticity in MDD and preclinical stress models. In particular, we will highlight the pro-depressive changes incurred by stress and the reversal of these changes by antidepressants, exercise, and diet.

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Figures

Figure 1
Figure 1
BDNF signaling pathways and opposing effects of stress, depression, exercise and antidepressants. BDNF binds to the TrkB receptor, resulting in autophosphorylation of tyrosine residues. These sites then interact to activate the MAPK, CaMKII, and PI3K signaling cascades. These pathways ultimately regulate multiple cellular systems, including neuronal survival, growth, and neuroplasticity, which can lead to alterations in antidepressant behavioral responses. Stress and depression decrease activation of these pathways, while antidepressants and exercise increase activation of these pathways. Abbreviations: BDNF, brain derived neurotrophic factor; TrkB, tropomyosin-related kinase B; MAPK, mitogen-activated protein kinase; CaMKII, calmodulin-dependent protein kinase; PI3K, phosphatidylinositol 3-kinase; Grb2, growth factor receptor-bound protein 2; GAB1, Grb2-associated binder-1; SOS, son of sevenless; Shc, Src homology 2-domain containing adaptor protein; PLCγ phospholipase C-γ; ERK, extracellular signal-regulated kinase; MEK, MAP/ERK kinase; MKP-1, MAP kinase phosphatase 1; PDK1, phosphoinositide dependent kinase 1; Akt, serine threonine kinase or protein kinase B; IP3, inositol triphosphate. Figure adapted from Duman and Voleti (2012).
Figure 2
Figure 2
Life timeline of genetic and environmental modulation of healthy emotional state or depression by BDNF and other neurotrophic factors. Genetic risk factors and stress can exacerbate depressive symptoms, while antidepressants, exercise, and diet may ameliorate depressive symptoms, in part, through the action of neurotrophic factors. This up- or down-regulation of BDNF by these environmental factors can shift the balance from depressed to healthy, and vice versa. Abbreviations: BDNF, brain derived neurotrophic factor.
Figure 3
Figure 3
Pathways mediating the regulation of the mTOR signaling cascade by novel rapid-acting antidepressants. Ketamine, an NMDA receptor antagonist, rapidly stimulates glutamate transmission and AMPA receptor activation, leading to activity-dependent release of BDNF. This leads to phosphorylation of ERK and Akt, subsequently regulating mTOR signaling. This can lead, through regulation of P70S6K and 4E-BP1, to increased translation and increased synaptic proteins, which contributes to increased synaptogenesis and antidepressant behaviors. Abbreviations: BDNF, brain derived neurotrophic factor; TrkB, tropomyosin-related kinase B; mTOR, mammalian _target of rapamycin; NMDA, N-methyl-D-aspartic acid; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; ERK, extracellular signal-regulated kinase; Akt, serine threonine kinase or protein kinase B; P70S6K, P70 ribosomal protein S6 kinase; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; TSC, tuberous sclerosis complex. Figure adapted from Duman and Voleti (2012).
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