PICK1-mediated glutamate receptor subunit 2 (GluR2) trafficking contributes to cell death in oxygen/glucose deprived hippocampal neurons

Oxygen and glucose deprivation (OGD) induces delayed cell death in hippocampal CA1 neurons, via Ca2+/Zn2+-permeable, GluR2-lacking AMPA receptors (AMPARs). Following OGD, synaptic AMPAR currents in hippocampal neurons show marked inward rectification and increased sensitivity to channel blockers selective for GluR2-lacking AMPARs. This occurs via two mechanisms: a delayed downregulation of GluR2 mRNA expression, and a rapid internalisation of GluR2-containing AMPARs during the OGD insult, which are replaced by GluR2-lacking receptors. The mechanisms that underlie this rapid change in subunit composition are unknown. Here, we demonstrate that this trafficking event shares features in common with events that mediate Long Term Depression (LTD) and Long Term Potentiation (LTP), and is initiated by the activation of NMDA receptors. Using biochemical and electrophysiological approaches, we show that peptides that interfere with PICK1 PDZ domain interactions block the OGD-induced switch in subunit composition, implicating PICK1 in restricting GluR2 from synapses during OGD. Furthermore, we show that GluR2-lacking AMPARs that arise at synapses during OGD as a result of PICK1 PDZ interactions are involved in OGD-induced delayed cell death. This work demonstrates a crucial role for PICK1 in the response to OGD that results in altered synaptic transmission and neuronal death, and has implications for our understanding of the molecular mechanisms that underlie cell death during stroke.