GDNF Selectively Induces Microglial Activation and Neuronal Survival in...
 

GDNF Selectively Induces Microglial Activation and Neuronal Survival in CA1/CA3 Hippocampal Regions Exposed to NMDA Insult through Ret/ERK Signalling

Francesca Boscia,1 Carla Lucia Esposito,2 Antonella Di Crisci,1 Vittorio de Franciscis,2 Lucio Annunziato,1* and Laura Cerchia2*
Received April 8, 2009; Accepted June 29, 2009.
http://www.pubmedcentral.nih.gov/art...?artid=2715099

Excerpts from the Introduction:

In vitro studies have shown that following GDNF binding to GFRα1 the resulting complex recruits Ret, leading to its activation by dimerization and autophosphorylation at specific cytoplasmic tyrosine residues, thus initiating a number of downstream intracellular pathways [3]. On the other hand, a Ret-independent pathway of GDNF signalling that involves the association of GFRα-1 with the p140NCAM isoform of the neural cell adhesion molecule (NCAM) and subsequent activation of Fyn and FAK kinases, has been as well demonstrated to take place in primary glial cells and neurons [4], [5].
In the last years a large number of studies demonstrated that GDNF provides potent neuroprotection in animal models of Parkinson's disease [6], motor neuron degeneration [7], [8], cerebral ischemia [9], and limbic seizure [10]. More importantly, the clinical use of GDNF for the treatment of the Parkinson's disease in humans is currently under evaluation [11]. The neuroprotective role of GDNF in the above mentioned neurodegenerative diseases lies on the widely recognized and potent pro-survival action on midbrain dopaminergic neurons [12], [13]; spinal cord motoneurons [7], [14], [15], noradrenergic neurons of the locus coeruleus [16], cerebellar Purkinje cells [17], cholinergic neurons of the basal forebrain [18], as well as peripheral sensory and autonomic neurons [19]. Interestingly, GDNF may exert trophic actions also in the hippocampus [20], a limbic region that is crucially involved in learning and memory processes. In addition, this region exhibits the distinctive feature of having neuronal populations which display differential vulnerability to several neurodegenerative stimuli [21]. Data obtained from in vivo studies indicated that GDNF and its receptors are widely expressed in the rat hippocampus [22]–[24]; furthermore, stroke, traumatic brain injury, or kainate-induces seizures significantly increases GDNF and their receptors mRNA expression in this limbic region [10], [25]. In vitro, GDNF has been found to protect hippocampal slice cultures and primary cortical neurons against toxic activation of the N-methyl-D-aspartate (NMDA) receptor [26], [27], where its application reduced the NMDA-induced calcium influx [27]. Although these studies suggest an important role for this trophic factor in this region following excitotoxic insults, the signalling pathways involved in GDNF-mediated neuroprotection in each hippocampal subfield and the identity of hippocampal cells that respond to GDNF stimulation still remains elusive.