Depresssion--emerging insights from neurobiology.
An emerging hypothesis suggests that the pathogenesis and treatment of depression is likely to involve a plasticity of neuronal pathways. The inability of neuronal systems to exhibit appropriate, adaptive plasticity could contribute to the pathogenesis of depression. Antidepressant treatments may exert their therapeutic effects by stimulating appropriate adaptive changes in neuronal systems. Recent studies have demonstrated that chronic antidepressant administration up-regulates the cAMP signal transduction cascade resulting in an increased expression and function of the transcription factor CREB. Enhanced CREB expression leads to an up-regulation of specific target genes, including the neurotrophin BDNF. Chronic antidepressant treatments enhance BDNF expression within hippocampal and cortical neurons and can prevent the stress-induced decrease in BDNF expression. Stress has been shown to: (i) induce neuronal atrophy/death; and (ii) decrease neurogenesis of hippocampal neurons. Clinical studies indicate significant hippocampal damage in cases of major, recurrent depression. It is possible that antidepressant treatments through enhanced expression of growth and survival promoting factors like BDNF may prevent or reverse the atrophy and damage of hippocampal neurons. Indeed, studies have indicated that chronic antidepressant treatments enhance hippocampal neurogenesis, promote neuronal sprouting and prevent atrophy. The molecular mechanisms underlying the effects of antidepressant treatments including adaptations in the cAMP transduction cascade, CREB and BDNF gene expression, and structural neuronal plasticity are discussed.
Vaidya
V A
VA
Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai, India.
Duman
R S
RS
D000223:Adaptation, Psychological; D000928:Antidepressive Agents / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002908:Chronic Disease; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology*; D015870:Gene Expression; D006801:Humans; D009473:Neuronal Plasticity; D018377:Neurotransmitter Agents / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D018377:Neurotransmitter Agents; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases