Pro-inflammatory cytokines, such as TNF-alpha, IL-1 and IL-6, were first discovered in the context of cellular activation and cell-to-cell communication in the immune system. Early studies on the role of cytokines in the brain suggested that their expression and activity is induced in response to an infection, head trauma, stroke or neurodegenerative diseases. Recently it has been demonstrated that rapid application of TNF-alpha induces surface expression of GluR1 subunit of AMPA receptors. Increased expression of GluR1 subunit of AMPA receptors (AMPAR) would increase Ca2+ permeability and may potentiate neuron death through an increased vulnerability to AMPAR-dependent excitotoxic stress. AMPAR containing GluR3 subunits are also Ca2+ permeable, in contrast to GluR2 containing receptors, however the effect of TNF-alpha on GluR3 subunit expression is not known. In this study we investigated the long-term effect of TNF alpha on regulation of membrane expression of GluR1, GluR2 and GluR3 AMPAR subunits. Rat primary hippocampal cultures were treated with various doses of TNF-alpha for different periods of time. At the end of the treatment changes in surface expression of AMPAR subunits were determined by biotinylation assay and western blotting. Treatment of hippocampal neurons with TNF-alpha (6nM and 60 nM) for 20 min or 1 day increased expression of GluR1 subunit of AMPAR (p<0.05), however no effect was observed after 3 days of treatment (p>0.05). Interestingly, preliminary data showed a trend of increase in GluR3 surface expression after 20 min of treatment with TNF-alpha (60nM). TNF-alpha (6nM and 60nM) applied for 20 min, 60 min, 1 day or 3 days had no effect on surface expression of GluR2 subunits (p>0.05).These findings suggest that TNF-alpha-induced increase in proportion of Ca2+ permeable AMPAR represents a novel molecular mechanism for neuron-glia interactions that might contribute to neurotoxicity in neuropathological conditions, associated with elevated levels of TNF-alpha.
| Schloesser, Robert J; Manji, Husseini K; Martinowich, Keri (2009) Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response. Neuroreport 20:553-7 |
