Physiological stress promotes adaptive plasticity, but the mechanisms responsible for maladaptation in the presence of an excessive or dysregulated response still remain unknown. Exposure to an acute inescapable foot shock (FS) stress protocol can induce both rapid and sustained changes in synaptic function and neuroarchitecture, suggesting that the effects of a single stressful event are far from being simply acute. Evaluating short- and long-term modifications triggered by acute stress could be a useful tool to dissect adaptive and maladaptive components underlying stress reaction. On this basis, the aim of the present thesis was to study some early and delayed alterations caused by acute FS stress in neuronal presynaptic (synaptosomes) and astroglia peri-synaptic (gliosomes) compartments purified from prefrontal cortex (PFC) in vulnerable (VUL) and resilient (RES) rats. We first applied the sucrose test paradigm, to identify RES or VUL rats at different time points after FS stress, thus showing that the anhedonic behaviour started 6h after FS stress and lasted at least for 48h. FS stress was characterized by an immediate and transient rise of corticosterone levels in both VUL and RES rats respect to controls. 24h after FS stress, when no augmentation of corticosterone level was still detectable, the depolarization-evoked glutamate release was more pronounced in PFC gliosomes of VUL, but not of RES rats. No release changes were found immediately, 6h and 48h after FS stress. No modifications were detected also in basal glutamate release in PFC gliosomes of both VUL and RES rats at each time point investigated. When focusing on PFC synaptosomes, we observed that the depolarization-evoked glutamate release was significantly increased in both VUL and RES rats respect to controls 24h after FS stress, while the basal glutamate release was increased in VUL animals only. Studying the molecular mechanisms underlying these functional alterations, we demonstrated that the excessive depolarization-evoked glutamate release measured 24h after FS-stress in VUL PFC gliosomes was mediated by glutamate transporters operating in the reverse mode. We also found that synapsin I expression did not change in synaptic membranes purified from PFC synaptosomes, while synapsin I phosphorylation in Ser9 was significantly increased in both RES and VUL rats, thus paralleling the increased glutamate release in PFC synaptosomes. Moreover, mineral corticoid receptors expression was significantly increased in RES rat PFC nuclear fraction whereas that of glucocorticoid receptors was increased in VUL rats. The present data suggest that acute FS stress induces adaptive/maladaptive stress responses at the synapse level, affecting the neuronal presynaptic counterpart and the surrounding astroglia cells with the alteration of specific molecular mechanisms that might represent new potential pharmacological targets for future therapeutic interventions.

Acute stress induces short- and long-lasting modifications of glutamate transmission in the prefrontal cortex at pre- and peri-synaptic compartments

FRUMENTO, GIULIA
2022

Abstract

Physiological stress promotes adaptive plasticity, but the mechanisms responsible for maladaptation in the presence of an excessive or dysregulated response still remain unknown. Exposure to an acute inescapable foot shock (FS) stress protocol can induce both rapid and sustained changes in synaptic function and neuroarchitecture, suggesting that the effects of a single stressful event are far from being simply acute. Evaluating short- and long-term modifications triggered by acute stress could be a useful tool to dissect adaptive and maladaptive components underlying stress reaction. On this basis, the aim of the present thesis was to study some early and delayed alterations caused by acute FS stress in neuronal presynaptic (synaptosomes) and astroglia peri-synaptic (gliosomes) compartments purified from prefrontal cortex (PFC) in vulnerable (VUL) and resilient (RES) rats. We first applied the sucrose test paradigm, to identify RES or VUL rats at different time points after FS stress, thus showing that the anhedonic behaviour started 6h after FS stress and lasted at least for 48h. FS stress was characterized by an immediate and transient rise of corticosterone levels in both VUL and RES rats respect to controls. 24h after FS stress, when no augmentation of corticosterone level was still detectable, the depolarization-evoked glutamate release was more pronounced in PFC gliosomes of VUL, but not of RES rats. No release changes were found immediately, 6h and 48h after FS stress. No modifications were detected also in basal glutamate release in PFC gliosomes of both VUL and RES rats at each time point investigated. When focusing on PFC synaptosomes, we observed that the depolarization-evoked glutamate release was significantly increased in both VUL and RES rats respect to controls 24h after FS stress, while the basal glutamate release was increased in VUL animals only. Studying the molecular mechanisms underlying these functional alterations, we demonstrated that the excessive depolarization-evoked glutamate release measured 24h after FS-stress in VUL PFC gliosomes was mediated by glutamate transporters operating in the reverse mode. We also found that synapsin I expression did not change in synaptic membranes purified from PFC synaptosomes, while synapsin I phosphorylation in Ser9 was significantly increased in both RES and VUL rats, thus paralleling the increased glutamate release in PFC synaptosomes. Moreover, mineral corticoid receptors expression was significantly increased in RES rat PFC nuclear fraction whereas that of glucocorticoid receptors was increased in VUL rats. The present data suggest that acute FS stress induces adaptive/maladaptive stress responses at the synapse level, affecting the neuronal presynaptic counterpart and the surrounding astroglia cells with the alteration of specific molecular mechanisms that might represent new potential pharmacological targets for future therapeutic interventions.
Acute stress; glutamate; prefrontal cortex; stress; ketamine; vulnerability; resilience; depression; anhedonia; synaptosomes; gliosomes; astrocytes
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/1066298
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