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

Abstract

The glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for several neuronal populations in different brain regions, including the hippocampus. However, no information is available on the: (1) hippocampal subregions involved in the GDNF-neuroprotective actions upon excitotoxicity, (2) identity of GDNF-responsive hippocampal cells, (3) transduction pathways involved in the GDNF-mediated neuroprotection in the hippocampus. We addressed these questions in organotypic hippocampal slices exposed to GDNF in presence of N-methyl-D-aspartate (NMDA) by immunoblotting, immunohistochemistry, and confocal analysis. In hippocampal slices GDNF acts through the activation of the tyrosine kinase receptor, Ret, without involving the NCAM-mediated pathway. Both Ret and ERK phosphorylation mainly occurred in the CA3 region where the two activated proteins co-localized. GDNF protected in a greater extent CA3 rather than CA1 following NMDA exposure. This neuroprotective effect targeted preferentially neurons, as assessed by NeuN staining. GDNF neuroprotection was associated with a significant increase of Ret phosphorylation in both CA3 and CA1. Interestingly, confocal images revealed that upon NMDA exposure, Ret activation occurred in microglial cells in the CA3 and CA1 following GDNF exposure. Collectively, this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF-induced Ret activation and neuroprotection, and suggest that, upon excitotoxicity, such neuroprotection involves a GDNF modulation of microglial cell activity.

Brain Infiltration of Leukocytes Contributes to the Pathophysiology of Temporal Lobe Epilepsy

“…Although microglial cell activation reflects CNS damage and can be deleterious (Rodgers et al, 2009;Haselkorn et al, 2010, Maroso et al, 2010, increasing evidence indicates that it can also be beneficial by increasing neurotrophic and antiinflammatory factors, clearing debris, and possibly promoting repair (Batchelor et al, 1999;Boscia et al, 2009;Rivest, 2009). Here, in line with the study by Siao et al (2003), demonstrating that microglia activation after intrahippocampal KA injection depends on tPA (tissue plasminogen activator) release from injured neurons, several indications suggest that microglia activation occurs as a consequence rather than a cause of KA-induced neurodegeneration.…”

Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1

“…The role of microglia in neuronal injury is a double-edged sword in that these cells can induce neuronal apoptosis via the triggering of an inflammatory response (58) but can also result in neuroprotection, which is not unlike macrophages in other tissues (59)(60)(61). The question as to which fate neurons will take in response to activated microglia most likely depends on the etiology of the injury.…”

The anti-inflammatory glycoprotein, CD200, restores neurogenesis and enhances amyloid phagocytosis in a mouse model of Alzheimer's disease

“…GDNF is more commonly recognized as a survival factor for dopaminergic neurons, as it promotes their survival, size, and neurite length in vitro (Lin, et al, 1993). However, GDNF also alters microglial activation and protects neurons in the hippocampus from excitotoxic insult (Boscia, et al, 2009). It may therefore play a role in proliferation and survival of microglia (Chang, et al, 2006,Honda, et al, 1999).…”