Tau controls NMDA receptor trafficking during homeostatic synaptic plasticity

Abstract

Homeostatic synaptic plasticity is essential for maintaining stable neural circuit function by preventing excessive neuronal excitation or inhibition. Chronic perturbation of neuronal activity triggers a compensatory modulation of the number of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors at the excitatory synapses. Previous research has primarily focused on AMPA receptors, yet the molecular mechanisms regulating the trafficking of NMDA receptors during homeostatic synaptic scaling remain unclear. Here we identify the microtubule-associated protein Tau as an essential molecule that mediates the synaptic upscaling of GluN2B-containing NMDA receptors during prolonged synaptic inactivity. Chronic activity blockade increases Tau phosphorylation at Ser-235 by cyclin-dependent kinase 5 (Cdk5), enhancing its interaction with and retention of active Fyn tyrosine kinase in the postsynaptic compartment. This promotes the phosphorylation of GluN2B at Tyr-1472, subsequently stabilising the expression of NMDA receptors on the neuronal plasma membrane. Finally, we showed that Tau pathology and disease-associated mutations in Tau and the GluN2B carboxyl-terminal tail disrupt the homeostatic synaptic upscaling of NMDA receptors following chronic neuronal silencing. Together, our findings identify a physiological role for Tau in homeostatic synaptic plasticity, the perturbation of which can lead to neuronal hyperexcitation, seizures and excitotoxic cell death.