1 Department of Clinical Medicine - Translational Neuropsychiatry Unit, Department of Clinical Medicine, Health, Aarhus University2 Department of Clinical Medicine - Stereological Research Laboratory, Department of Clinical Medicine, Health, Aarhus University3 Department of Clinical Medicine - Electron Microscopy Laboratory, Department of Clinical Medicine, Health, Aarhus University4 unknown5 Department of Clinical Medicine - Stereological Research Laboratory, Department of Clinical Medicine, Health, Aarhus University6 Department of Clinical Medicine - Translational Neuropsychiatry Unit, Department of Clinical Medicine, Health, Aarhus University
Background: Limbic structures where glutamatergic transmission is considered to be prevalent such as amygdala, hippocampus and prefrontal cortex, have shown a deep impairment in stress-related disorders . A number of studies have highlighted the cumulative effects of stress and its major mediators, glucocorticoids, on brain volume and dendritic remodeling, in both humans and rodents. Nevertheless, few is still known on the structural changes exerted by behavioral stress on the features of glutamatergic synapses as sites of neuronal communication. Indeed, in excitatory synapses synaptic communication is driven by neurotransmitter which is stored, within the presynaptic terminal, in morphologically distinct pools of vesicles, namely the readily-releasable pool of vesicles (RRP), docked to the active zone and ready for release, and the reserve pool of vesicles. When neurotransmitter is released, exchange of informations takes place through interaction of glutamate with receptors sitting on the post-synaptic density. Alterations of such synaptic ultrastructure might underlie following impairment of glutamatergic release and transmission. Aim: Main goal of the present study was therefore to shade light on the consequences of an acute and shorttermed stressor on medial prefrontal cortex (mPFC) ultrastructure. Effects of antidepressant desipramine administered chronically previous to stress was also assessed. Methods: Rats were treated chronically with either desipramine (DMI) or vehicle (2 weeks); at the end of the treatment animals were subjected to acute Foot-Shock (FS) stress and soon after they were deeply anesthetized and perfused. mPFC subareas (prelimbic area, dorsal anterior cingulate and medial precentral area) were identified, based on their noticeable citoarchitectural features, and overall volume quantified . Distribution of glutamatergic synaptic terminals was evaluated with immunohistochemistry. Asymmetric-glutamatergic synapses were identified and the size of readilyreleasable pool and reserve-pool of vesicles estimated, through serial section electron microscopy. Extension of post-synaptic density as well as of active zone area was measured; presynaptic terminal volume was also assessed. Results: Glutamatergic synapses were found to be the majority within mPFC. Acute behavioral stress selectively induced a strong increase in the number of vesicles docked to the membrane and ready for release: only a specific population of glutamatergic synapsesubtypes was affected. The stress-induced increase in the number of docked vesicles was partially prevented by chronic treatment with DMI. Moreover, following acute stress volume of presynaptic glutamatergic terminals was also reduced. No effects was observed on the volume of medial prefrontal cortex. Conclusions: In the present study we proved ultrastructural evidence that acute stress was able to deeply challenge the structure of glutamatergic terminals' in a matter of one hour. Previous treatment with chronic DMI seemed to only partially prevent such stressinduced changes. Identifying the effects of stress on excitatory transmission will provide further knowledge in developing drugs directly targeting the glutamatergic system.
Acta Neuropsychiatrica, 2013, Vol 25, Issue 1
desipramine neurotransmitter glutamic acid receptor glucocorticoid antidepressant agent prefrontal cortex college psychopharmacology ultrastructure synapse postsynaptic density acute stress behavioral stress nerve ending interpersonal communication rodent sitting human brain size hippocampus population membrane electron microscopy immunohistochemistry anterior cingulate footshock rat long term care shade diseases amygdaloid nucleus