INTERLEUKIN-1BETA AND NMDA RECEPTOR: A BRIDGE BETWEEN INFLAMMATION AND THE GLUTAMATERGIC SYSTEM
Tesi di Dottorato
Data di Pubblicazione:
2012
Citazione:
INTERLEUKIN-1BETA AND NMDA RECEPTOR: A BRIDGE BETWEEN INFLAMMATION AND THE GLUTAMATERGIC SYSTEM / M. Boraso ; tutor: B. Viviani ; coordinatore: G. Franceschini. Universita' degli Studi di Milano, 2012 Feb 08. 24. ciclo, Anno Accademico 2011. [10.13130/boraso-mariaserena_phd2012-02-08].
Abstract:
Interleukin (IL)-1β, originally described as an immune cell mediator in the periphery, has been involved in the modulation of several neurological functions and dysfunctions (Rothwell and Hopkins, 1995; Viviani et al., 2007). IL-1β is involved in processes like regulation of sleep-wake cycle, control of synaptic activity, LTP maintenance/inhibition, and is implicated in several pathological conditions like ischemia, excitotoxic injury, Alzheimer’s disease, HIV-dementia complex, epilepsy, neuropathic pain. Recently IL-1β has been indicated as important mediator in neuroendocrine and neurobehavioral stress response (Goshen and Yirmya, 2009) and to play a role in psychiatric disorders like schizophrenia (Meyers et al. 2011). While the initial trigger for acute injury or chronic disease may differ between neurological disorders, the resulting pathology may involve overlapping, if not identical, mechanisms. As such, a better understanding of the molecular mechanisms that underlie the action of this cytokine within the CNS might facilitate the development of promising therapeutics in the field of CNS disorders.
The biochemical pathways by which this cytokine contributes to brain dysfunction and injury remains largely unidentified. Substantial evidence suggests the existence of a reciprocal functional interaction between IL-1β and NMDA receptors (NMDARs) (Fogal et al. 2008; Hagan et al., 1996; Loddick and Rothwell, 1996 Vezzani et al., 1999).
NMDARs are glutamate-gated ion channel widely expressed in the central nervous system (CNS) and play key roles in excitatory synaptic transmission. They are essential mediators of many forms of synaptic plasticity and molecular mechanisms of cognition (Aamodt, 1999; Bliss et al., 1993). NMDARs are also key mediators of glutamate exicitotoxicity associated in acute neurological traumas as stroke, or in chronic neurodegeneration disease, including Huntington’s disease, Alzheimer’s diseases (Triller and Coquet, 2005). Based on these observations, in 2003 we hypothesized the existence of a functional relationship between IL-1β and the NMDAR that could in a way provide a molecular mechanism to several features common to both neurodegenerative and psychiatric disorders. We actually demonstrated, that recombinant IL-1β induces the activation of Src family kinases and the subsequent phosphorylation at Tyr-1472 of GluN2B subunit of NMDAR (Viviani et al., 2003) in primary hippocampal neurons. The activation of this pathway potentiates NMDA-induced intracellular Ca2+ increase and also exacerbates NMDA-induced neuronal death in vitro (Viviani et al., 2003).
Thus, these results confirmed our hypothesis suggesting that hippocampal neurons exposed to IL-1β are more susceptible to glutamatergic excitation through the NMDA receptor component. Furthermore, this findings suggest that the recruitment of IL-1β/NMDAR cross-talk could provide the missing link to understand the events implicated in the convergence of these to systems.
Due to: (i) the relevance of these two systems in the regulation of neuronal functions and in inducing susceptibility of neuronal impairment and decline, and (ii) the potential therapeutic implications, we thought to better define the molecular mechanisms that regulate the IL-1β/NMDAR cross talk by using both in vitro and in vivo approaches.
We thus investigated (i) the effect of native IL-1β generated in an in vitro model of neurotoxicity on NMDAR and the impact on neuronal organization and survival; (ii) the distribution of IL-1RI and the associated signalling proteins, IL-1RAcP and MyD88, in rat hippocampal subcellular compartments, both in physiological and pathological conditions and (iii) the dynamical interaction existing between IL-1RI and NMDAR (iv) the possibl
Tipologia IRIS:
Tesi di dottorato
Keywords:
interleukin-1beta ; NMDA receptor ; inflammation
Elenco autori:
M. Boraso
Link alla scheda completa:
Link al Full Text: