Changing synapses to treat depression : a translational approach
Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences INSERM U894 / Faculté de Médecine Université Paris Descartes Paris, France
The pathophysiology of stress-related disorders, such as depression, involves reductions in neuronal connectivity in specific limbic circuits. Imaging brain activity from patients suffering from depression has largely pointed to functional alterations of brain networks that highlight the subgenual cingulate and the amygdala-hippocampus complex. Neuronal plasticity is likely to be an important mechanistic component of those malfunctioning cortical networks. In rodents, the so called prelimbic/infralimbic cortex represents the apparent homolog of the medial and subgenual prefrontal cortex in humans that have extensive connections with subcortical regions like the hippocampus and the amygdala.
In recent work, we demonstrated that exposure to stress and even brief periods of stress in animals is sufficient to cause impairment in synaptic plasticity in prefrontal networks by reducing long-term potentiation (LTP) in the hippocampal outflow to the prefrontal cortex. Antidepressants reverse the stress-induced changes in prefrontal plasticity, but with marked differences in efficacy depending on their mode of action. We then examined the effects of pharmacologically distinct, antidepressants, on stress-induced synaptic alterations in frontal cortex. Altered synaptic functioning is linked to dysfunctions in signalling cascades, receptor regulation and transcription factors that are key regulators of synaptic plasticity and these changes are dependent on glucocorticosteroids. The data indicate a potential effect on AMPA receptor (AMPAR) phosphorylation as a possible mechanism of the reversal of LTP by specific antidepressants. We further investigated the effects of stress on the different AMPAR subunits in different limbic regions (prefrontal cortex, hippocampus, amygdala) and found changes in AMPAR functioning that are subunit and brain region specific. Thus, from a therapeutic point of view, these results put forward a region-oriented approach.
Stress plays key roles in the pathophysiology of affective disorders and a balanced interplay between the three core limbic regions may predict the stress symptoms in human. Understanding these adaptations, particularly those changes that are sensitive to psychotropic drugs, is important for the development of more potent and specific treatments of depression. Efforts are under way to combine research in both human and animals and this interchange between basic animal models and human pathophysiology should help to refine understanding of these complex psychiatric disorders.