Functional and Structural Remodeling of Glutamate Synapses in Prefrontal and Frontal Cortex Induced by Behavioral Stress

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.

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

“…While there is no definitive consensus by which antidepressants work, prevailing theories suggest that therapies target maladaptive synaptic circuitry [70]. Regions implicated in neuropsychiatric disease that are of particular importance include the hippocampus, a limbic structure involved in learning, memory, and stress response, and the prefrontal cortex, which has vast connections with monoaminergic- and mood-regulating areas.…”

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…Stress has a biphasic effect on glutamatergic transmission that is mirrored in its effects on dendritic arborization and spine density of pyramidal neurons in the PFC. The effects of stress on glutamatergic transmission in the PFC and on pyramidal cell morphology and excitatory synapse number have been comprehensively reviewed (Popoli et al, 2011;Musazzi et al, 2015). Acute stress increases prefrontal glutamatergic transmission and enhances dendritic complexity and spine density of pyramidal neurons, often accompanied by mild cognitive enhancement (Musazzi et al, 2015).…”

“…The effects of stress on glutamatergic transmission in the PFC and on pyramidal cell morphology and excitatory synapse number have been comprehensively reviewed (Popoli et al, 2011;Musazzi et al, 2015). Acute stress increases prefrontal glutamatergic transmission and enhances dendritic complexity and spine density of pyramidal neurons, often accompanied by mild cognitive enhancement (Musazzi et al, 2015). Chronic stress causes dendritic atrophy of these same neurons in the PFC (Cook and Wellman, 2004;Radley et al, 2006).…”

Optogenetic Control of Spine-Head JNK Reveals a Role in Dendritic Spine Regression

“…Structural plasticity of dendritic spines facilitates elimination and regrowth of synapses and provides a fundamental process for adaptive neurotransmission. Understanding the underlying mechanism is relevant for memory and learning but also for pathologies such as depression, where significant spine loss is a hallmark (Duman and Duman, 2015;Musazzi et al, 2015;Varidaki et al, 2016). Here, we identify using an optogenetic approach, that catalytically active JNK controls spine stability from within the spine-head.…”