Abstract
BackgroundHyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer’s disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear.MethodsWe established a cell-based assay to quantify excitotoxicity in primary cultures of mouse hippocampal neurons and investigated the role of tau in exicitotoxicity by modulating neuronal tau expression through genetic ablation or transduction with lentiviral vectors expressing anti-tau shRNA or constructs encoding wildtype versus mutant mouse tau.ResultsWe demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca2+ influx and neurotoxicity in neurons from wildtype mice. Conversely, expression of wildtype mouse tau enhances Ca2+ influx and excitotoxicity in tau-deficient (Mapt−/−) neurons. Reconstituting tau expression in Mapt−/− neurons with mutant forms of tau reveals that the tau-related enhancement of Ca2+ influx and excitotoxicity depend on the phosphorylation of tau at tyrosine 18 (pY18), which is mediated by the tyrosine kinase Fyn. These effects are most evident at pathologically elevated concentrations of glutamate, do not involve GluN2B–containing NMDA receptors, and do not require binding of Fyn to tau’s major interacting PxxP motif or of tau to microtubules.ConclusionsAlthough tau has been implicated in diverse neurological diseases, its most pathogenic forms remain to be defined. Our study suggests that reducing the formation or level of pY18-tau can counteract excitotoxicity by diminishing NMDA receptor-dependent Ca2+ influx.
Highlights
Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways
Blockers, expression of mTauY18F increased NMDARdependent Ca2+ influx less than expression of mTauWT (Fig. 6f ). These results suggest that tau promotes glutamateinduced excitotoxicity by increasing NMDA receptor (NMDAR)-dependent Ca2+ influx and that Fyn-mediated phosphorylation of tau at Y18 enhances this process at high concentrations of glutamate
At lower concentrations of glutamate, tau reduction had no effect on multiple outcome measures, including NMDAinduced Ca2+ influx. These observations are consistent with in vivo studies demonstrating that reduction or ablation of tau has minimal or no effects on neuronal activities unless pathological conditions are introduced that cause network hyperexcitability [1,2,3,4,5,6, 86]. While these studies indicate that tau reduction counteracts network hyperexcitability of diverse causes, the current study suggests that tau reduction may counteract the excitotoxic neuronal injury to which network hyperexcitability can lead, highlighting the broad potential of this therapeutic strategy
Summary
Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer’s disease (AD). Network hyperexcitability can lead to excessive release of excitatory neurotransmitters such as glutamate, which can cause neuronal injury and degeneration by overactivating NMDA-type glutamate receptors (NMDARs) and related signaling pathways (excitotoxicity) [11, 12]. More work is needed to define the roles of tau and tau reduction in excitotoxicity
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