Prolonged systemic inflammation persistently modifies synaptic plasticity in the hippocampus: Modulation by the stress hormones

Transient systemic inflammation has been shown to cause altered behavior both in humans and in laboratory animals through activation of microglia and heightened level of cytokines detected in the brain and in the body. Furthermore, both activated microglia and the increased cytokines level have been associated with the sudden clinical deterioration in demented people or in aged patients upon systemic inflammation. Whilst it is increasingly becoming clear the role of transient systemic inflammation in promoting dementia in aged individuals, it is still a matter of debate whether prolonged systemic inflammation might persistently modify the brain. In this study, we examined the influence of a systemic long term inflammatory event on synaptic plasticity. We report that while a short exposure to LPS produces transient deficit in long term potentiation (LTP) expression, systemic prolonged inflammation impairs LTP in slices of animals previously primed by a Complete Freund’s adjuvant injection. Interestingly, steroids are able to modulate this effect: whereas glucocorticosteroid (GR) activation further reduces LTP, mineralocorticosteroid receptors (MR) activation promotes the full recovery of LTP. We believe that this research advances the current understandings on the role of the immune system in the onset and progression of cognitive deficits following long lasting systemic inflammation, and proposes possible insights on future strategies in order to prevent early dementia in these predisposed individuals

Steroid modulation of hippocampal plasticity: switching between cognitive and emotional memories.

Several new observations have shifted the view of the hippocampus from a structure in charge of cognitive processes to a brain area that participates in the formation of emotional memory. Specifically, while the dorsal hippocampus is involved in the processing of cognitive memories; the ventral sector is mainly associated with the control of behavioral inhibition, stress and emotional memory.Stress is likely to cause this switch in control of hippocampal functions by modulating synaptic plasticity in the dorsal and ventral sectors of the hippocampus through the differential activation of either mineralocorticosteroid (MR) or glucocorticosteroid (GR) receptors. Herein, we will review the effects of stress hormones on synaptic plasticity in the hippocampus and will try to outline the outcomes on stress-related global functions of this structure. We will propose that steroid hormones act as molecular switches: by changing the strength of synaptic connectivity in the hippocampus following stress, and that they regulate the routes by which the hippocampus is functionally linked to the rest of the brain. This hypothesis has profound implications for the pathophysiology of psychiatric disorders

Treating seizures and epilepsy with anticoagulants?

Thrombin is a serine protease playing an essential role in the blood coagulation cascade. Recent work, however, has identified a novel role for thrombin-mediated signaling pathways in the central nervous system. Binding of thrombin to protease-activated receptors (PARs) in the brain appears to have multiple actions affecting both health and disease. Specifically, thrombin has been shown to lead to the onset of seizures via PAR-1 activation. In this perspective article, we review the putative mechanisms by which thrombin causes seizures and epilepsy. We propose a potential role of PAR-1 antagonists and novel thrombin inhibitors as new, possible antiepileptic drugs

Thrombin regulation of synaptic transmission and plasticity: implications for health and disease.

Thrombin, a serine protease involved in the blood coagulation cascade has been shown to affect neural function following blood-brain barrier breakdown. However, several lines of evidence exist that thrombin is also expressed in the brain under physiological conditions, suggesting an involvement of thrombin in the regulation of normal brain functions. Here, we review ours’ as well as others' recent work on the role of thrombin in synaptic transmission and plasticity through direct or indirect activation of Protease-Activated Receptor-1 (PAR1). These studies propose a novel role of thrombin in synaptic plasticity, both in physiology as well as in neurological diseases associated with increased brain thrombin/PAR1 levels