부산대학교 도서관

Global cerebral ischemia is a debilitating injury that damages the CA1 region of the hippocampus, an area important for learning and memory. Protein kinase C epsilon (PKC[Latin Small Letter Open E]) activation is a critical component of many neuroprotective treatments. The ability of PKC[Latin Small Letter Open E] activation to regulate AMPA receptors (AMPARs) remains unexplored despite the role of AMPARs in excitotoxicity after brain ischemia. We determined that PKC[Latin Small Letter Open E] activation increased expression of a protein linked to learning and memory, activity-regulated cytoskeleton-associated protein (arc). Also, arc is necessary for neuroprotection and confers protection through decreasing AMPAR currents via GluR2 internalization. In vivo, activation of PKC[Latin Small Letter Open E] increased arc expression through a BDNF/TrkB pathway, and decreased GluR2 mRNA levels. In hippocampal cultured slices, PKC[Latin Small Letter Open E] activation decreased AMPAR current amplitudes in an arc- and GluR2-dependent manner. Additionally, PKC[Latin Small Letter Open E] activation triggered an arc- and GluR2 internalization-dependent delay in latency until anoxic depolarization. Inhibiting arc also blocked PKC[Latin Small Letter Open E]-mediated neuroprotection against lethal oxygen and glucose deprivation. These data characterize a novel PKC[Latin Small Letter Open E]-dependent mechanism that for the first time defines a role for arc and AMPAR internalization in conferring neuroprotection.