Fig. 10
From: Tau exacerbates excitotoxic brain damage in an animal model of stroke
Schematic of excitotoxic, NMDAR-mediated Ras/ERK signaling in tau+/+ and tau−/− mice. In wild-type mice (tau+/+), excessive synaptic glutamate (glut) levels trigger increased calcium (Ca2+) influx via NMDARs at the post-synapse. This triggers Ras activation by GTP binding, and eventually activation (phosphorylation; P) of ERK via the Ras/Raf/MEK/ERK cascade. To allow for Ras activation, levels of the site-specific inhibitor SynGAP1 (red) that resides in a complex with PSD-95 and tau need to be controlled (a process we found to be dependent directly or indirectly on tau). In contrast, our data revealed absence of excitotoxic Ras activation and hence downstream ERK phosphorylation in tau−/− mice. In the absence of tau, SynGAP1 is increasingly bound to PSD-95 and completely suppresses site-specific NMDAR-mediate activation of Ras at the post-synapse. As a consequence, neuronal damage and activation of immediate-early genes (IEGs) after stroke and excitotoxic seizures are suppressed
