Proceedings of The Physiological Society
King's College London (2011) Proc Physiol Soc 22, PC31
C. A. Puddifoot1, M. Martel1, D. J. Wyllie1, G. E. Hardingham1
1. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
There is strong evidence that disruption of mitochondrial biogenesis and function play a causal role in neuronal vulnerability in neurodegeneration1. Indeed selective loss of highly metabolic regions of the brain in Huntington’s disease (HD) suggest a link between mitochondrial dysfunction and oxidative stress in disease pathogenesis. The transcriptional coactivator PPARgamma coactviator 1alpha (PGC-1α) is a regulator of mitochondrial biogenesis and function2,3 and is decreased in the striatum of patients with HD. Furthermore PGC-1α undergoes targeted downregulation by mutant huntingtin protein (mHtt)2 and PGC-1α knockout mice have striatal lesions similar to mHtt mice4. In addition, PGC-1α partially reverses the toxic effects of mutant huntingtin in cultured striatal neurones2 while in vivo administration of PGC-1α to the striatum in a mouse model of HD reduces neuronal volume loss2. Synaptic NMDAR-activity can drive the expression of PGC-1α which is neuroprotective against oxidative and excitotoxic stress in vitro (Soriano et al. (2011) Antioxidants & Redox Signaling in press), whereas extrasynaptic NMDAR expression is increased in HD5. Excessive NMDAR activity leads to excitoxic death in neurones and its regulation has been targeted in the search for therapeutic interventions for multiple neurological disorders. This study proposes a novel mechanism of neuroprotection provided by PGC-1α via the regulation of glutamate receptor expression. Electrophysiological whole-cell patch-clamp recordings from rat primary cortical neuronal cultures (days in vitro 9-11) indicated that over expression of PGC-1α caused a 29.5 ± 6.0% decrease (N=6, n=24, t-test p < 0.05) in whole-cell NMDAR-mediated currents in response to bath application of NMDA (100 µM). Conversely, siRNA knock-down of PGC-1α caused a 48.7 ± 13.4% (N=6, n=26, t-test p < 0.05) increase in whole-cell NMDAR-mediated currents. Increased expression of PGC-1α also caused a significant decrease (26.3 ± 5.8%, N=3, n=12, t-test p < 0.05) in whole-cell AMPAR-mediated currents together with a reduction in the gene promoter activity of GluA1 and GluA2 AMPAR subunits (36.1 ± 3.6% and 18.0 ± 5%, respectively, n=5, t-test p<0.05). In conclusion our data suggests PGC-1α can regulate the functional expression of both NMDA and AMPA ionotropic glutamate receptor subtypes. Such regulation many contribute to the control of neuronal survival.
Where applicable, experiments conform with Society ethical requirements