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Abstract
Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau−/−) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau−/− mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.
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1 Dementia Research Unit (DRU), School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia
2 Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics & Differentiation, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore; The Jenner Institute, University of Oxford, Oxford, UK
3 Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia
4 Neuron Culture Core Facility (NCCF), The University of New South Wales, Sydney, NSW, Australia
5 Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics & Differentiation, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
6 Neuron Culture Core Facility (NCCF), The University of New South Wales, Sydney, NSW, Australia; Neurodegeneration and Repair Unit (NRU), School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia
7 Dementia Research Unit (DRU), School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia; Transgenic Animal Unit, Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, NSW, Australia; Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia