Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression

Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2485-94. doi: 10.1098/rstb.2012.0212.


The monoamine hypothesis of depression has dominated our understanding of both the pathophysiology of depression and the action of pharmacological treatments for the last decades, and it has led to the production of several generations of antidepressant agents. However, there are serious limitations to the current monoamine theory, and additional mechanisms, including hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, as well as neurodegenerative and inflammatory alterations, are potentially associated with the pathogenesis of mood disorders. Moreover, new data have recently indicated that epigenetic mechanisms such as histone modifications and DNA methylation could affect diverse pathways leading to depression-like behaviours in animal models. In a transgenic mouse model of depression, in which a downregulation of glucocorticoid receptors (GR) causes a deficit in the HPA axis feedback control, besides alterations in monoamine neurotransmission and neuroplasticity, we found modifications in the expression of many proteins involved in epigenetic regulation, as well as clock genes, in the hippocampus and the frontal cortex, that might be central in the genesis of depressive-like behaviours.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Depression / drug therapy
  • Depression / physiopathology*
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Hippocampus / drug effects
  • Hippocampus / physiopathology
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity*
  • Neurotransmitter Agents / metabolism
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / metabolism
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Receptors, Glucocorticoid / physiology
  • Serotonin / metabolism
  • Synaptic Transmission


  • Antidepressive Agents
  • Neurotransmitter Agents
  • Receptors, Glucocorticoid
  • Serotonin
  • CLOCK Proteins
  • Clock protein, mouse