Abstract
Increasing evidence has shown that the pathophysiology of neuropsychiatric disorders, including mood disorders, is associated with abnormal function and regulation of the glutamatergic system. Consistently, preclinical studies on stress-based animal models of pathology showed that glucocorticoids and stress exert crucial effects on neuronal excitability and function, especially in cortical and limbic areas. In prefrontal and frontal cortex, acute stress was shown to induce enhancement of glutamate release/transmission dependent on activation of corticosterone receptors. Although the mechanisms whereby stress affects glutamate transmission have not yet been fully understood, it was shown that synaptic, non-genomic action of corticosterone is required to increase the readily releasable pool of glutamate vesicles, but is not sufficient to enhance transmission in prefrontal and frontal cortex. Slower, partly genomic mechanisms are probably necessary for the enhancement of glutamate transmission induced by stress. Combined evidence has suggested that the changes in glutamate release and transmission are responsible for the dendritic remodeling and morphological changes induced by stress and it has been argued that sustained alterations of glutamate transmission may play a key role in the long-term structural/functional changes associated with mood disorders in patients. Intriguingly, modifications of the glutamatergic system induced by stress in the prefrontal cortex seem to be biphasic. Indeed, while the fast response to stress suggests an enhancement in the number of excitatory synapses, synaptic transmission and working memory, long-term adaptive changes – including those consequent to chronic stress – induce opposite effects. Better knowledge of the cellular effectors involved in this biphasic effect of stress may be useful to understand the pathophysiology of stress-related disorders, and open new paths for the development of therapeutic approaches.
Highlights
Starting from the evidence of the antidepressant properties of drugs increasing the availability of monoamines, the pathophysiology of mood and anxiety disorders has been linked for manyStress-induced functional/structural remodeling years to alterations in monoaminergic transmission [1, 2]
We focus on the functional alterations in the glutamate system and in dendritic reorganization and neuronal connectivity in the prefrontal cortex (PFC) [a brain region critical for working memory, executive function, and extinction of learning, Ref. [9]], reported in patients with mood disorders and induced by stress in preclinical models
The Increase of Glutamate Transmission and Release in Prefrontal Cortex is Mediated by Slower, Likely Genomic, Corticosterone Effect Acute stressors of diverse types, including acute forced swim, acute restraint, and elevated-platform stress, as well as acute corticosterone treatment of rats, were shown to induce in PFC pyramidal neurons a significant long-lasting potentiation, starting 1 h after stress and sustained for up to 24 h after cessation of stress, of glutamatergic transmission and an increase of surface NMDA and AMPA receptor subunits level, through the activation of glucocorticoid receptors [87]. This was the first evidence showing that corticosterone is necessary and sufficient for increasing glutamate transmission in PFC, and suggested that the potentiation of glutamate transmission in this brain area involves delayed mechanisms
Summary
In prefrontal and frontal cortex, acute stress was shown to induce enhancement of glutamate release/transmission dependent on activation of corticosterone receptors. The mechanisms whereby stress affects glutamate transmission have not yet been fully understood, it was shown that synaptic, non-genomic action of corticosterone is required to increase the readily releasable pool of glutamate vesicles, but is not sufficient to enhance transmission in prefrontal and frontal cortex. Combined evidence has suggested that the changes in glutamate release and transmission are responsible for the dendritic remodeling and morphological changes induced by stress and it has been argued that sustained alterations of glutamate transmission may play a key role in the long-term structural/functional changes associated with mood disorders in patients.
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