The stress impact on glutamate transmission: a key to mood and anxiety disorders

Dysfunction of the glutamate system is increasingly considered a core feature of neuropsychiatric disorders, including mood and anxiety disorders. Neuroimaging studies have shown consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent stress/depression models found dendritic remodeling/reduction of synapses in the same areas, suggesting these changes are major factors in psychopathology. Additional studies have shown that antidepressants may partly reverse maladaptive changes in synapses/circuitry of rodent models. Destabilization of glutamate release/transmission in cortical/limbic areas, in turn induced by stress and glucocorticoids, seems to be crucial for these structural/functional changes [1]. We have previously shown that acute stress induces rapid enhancement of depolarization-evoked glutamate release/transmission in prefrontal and frontal cortex (PFC/FC), by increasing corticosterone levels and stimulation of synaptic glucocorticoid/mineralocorticoid receptors (GR/MR). In addition, we have shown that chronic antidepressants are able to prevent the enhancement of glutamate release induced by acute stressors [2]. We have now evidence that acute stress rapidly enhances glutamate vesicles mobilization and increases the readily releasable pool size, through activation of synaptic GR/MR-mediated non-genomic mechanisms. In vitro application of corticosterone to purified PFC/FC synaptosomes mimics vesicles mobilization, but does not enhance depolarization-dependent glutamate release and transmission. Our results suggest that rapid (non-genomic) synaptic action of corticosterone on the RRP size is necessary, but not sufficient, to increase glutamate release/transmission in PFC/FC. Enhancement of glutamate release/transmission likely needs the activation of delayed, possibly genomic, mechanisms. These studies may help defining new targets for pharmacological treatments of mood and anxiety disorders.