The impact of stress on glutamate transmission and neuronal architecture. A key to pathophysiology and treatment of mood and anxiety disorders

In the past decade it has become increasingly acknowledged that maladaptive changes in the structure and function of excitatory/inhibitory circuitry (representing the vast majority of neurons and synapses in brain) have a primary role in the pathophysiology of mood and anxiety disorders, particularly major depression. Indeed, clinical research has shown alterations in levels, clearance and metabolism of glutamate in mood and anxiety disorders, and neuroimaging studies showed consistent volumetric changes in brain areas where glutamate neurons and synapses predominate. In parallel, rodent studies have shown that stressors induce dendritic atrophy, reduction of synapses number and volumetric reductions resembling those observed in patients with mood disorders. A major role in this process is attributed to elevation of glucocorticoid hormones by stressors, which enhance glutamate release/transmission, in turn inducing retraction of dendrites. Converging evidence from various groups, including ours, has shown that enhancement of glutamate release/transmission in cortical/limbic areas, in turn induced by stress and glucocorticoids, is crucial for these structural/functional changes. We have shown that acute stress rapidly enhances glutamate release/transmission in prefrontal and frontal cortex (PFC/FC), mediated by glucocorticoid/mineralocorticoid receptors (GR/MR). We have now evidence that acute stress rapidly enhances glutamate vesicles mobilization, through activation of synaptic GR/MR-mediated non-genomic mechanisms. Our results suggest that rapid (non-genomic) synaptic action of corticosterone is necessary, but not sufficient, to increase glutamate release/transmission in PFC/FC, which requires activation of delayed, genomic, mechanisms. In addition, antidepressants are able to prevent the enhancement of glutamate release induced by acute stressors. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression animal models. Furthermore, recent compelling evidence has shown that the glutamate system is also a target for rapid acting antidepressants, such as NMDA receptor antagonists. A comprehensive, integrated analysis of the stress- and drug-induced changes in excitatory transmission (representing over 80% of circuitry in cortical and limbic brain areas) may supply crucial information as to how adaptive/maladaptive changes may determine the fate of cognition and affect at the boundary between normal function and mental illness.