Researchers led by YouMing Lu published their findings in the July 8, 2004, issue of Neuron, showing why particular neurons in the hippocampus are more prone to death during stroke. The hippocampus is a brain region central to the formation of memories.
Lu and his colleagues concentrated their studies on receptors called AMPA receptors, which are channels in the membranes of neurons that control the flow of calcium into the cell. Such receptors, along with others, called NMDA receptors, have been known to be involved in rendering neurons vulnerable to death from oxygen starvation, or ischemia, in stroke.
However, clinical trials of drugs to treat stroke by generally blocking AMPA and NMDA receptors have failed, because the drugs also block those receptors in the multitude of neurons that are not vulnerable to death from stroke.
Lu and his colleagues sought to understand what specific features of AMPA receptors render particular hippocampal neurons vulnerable. Such vulnerable neurons are distinguished by the fact that their AMPA channels open to allow a cascade of calcium and zinc into the cells. In turn, this calcium and zinc flow likely triggers machinery within the cell that activates NMDA channels, which causes neuronal death.
Seeking to understand the molecular basis for this AMPA channel behavior, the researchers traced this AMPA channel opening to a subunit of the channel protein, called GluR2, that dictates the channel's permeability to calcium.
Their experiments showed that they could prevent injury to the vulnerable cells in rat brain by introducing a form of GluR2 that renders the AMPA receptors impermeable to calcium. What's more, they found that another form of GluR2 that keeps the channels open caused death in brain cells that were otherwise resistant to ischemia.
Other researchers had also discovered that ischemia caused a reduction in the activity of the gene for the protein, called CREB, that controls the gene producing GluR2. Sure enough, when Lu and his colleagues inserted a version of the CREB gene that was always activated, it protected the vulnerable neurons from ischemia.
The researchers also traced the effects of calcium influx into the vulnerable cells, discovering that the calcium entry though AMPA channels enhances activity of an enzyme called Cdk5, which activates NMDA receptors. When they blocked calcium, they found that NMDA receptor activity was blocked.
"Our studies selectively targeted the pathological effects of AMPA receptors by inhibiting the [calcium] permeability of AMPA receptor channels exclusively, leaving [calcium]-impermeable AMPA receptors unaffected," concluded the researchers. "Therefore, this work suggests that the GluR2 subunit is a promising therapeutic target for stroke." What's more, wrote the researchers, since the neuronal damage in amyotrophic lateral sclerosis also results from calcium-permeable AMPA channels, "it is likely that a similar therapeutic approach may be applied to this disease."
ShuHong Liu, Lorraine Lau, JianShe Wei, DongYa Zhu, Shengwei Zou, Hong-Suo Sun, YangPing Fu, Fang Liu, and YouMing Lu: "Expression of Ca2+-Permeable AMPA Receptor Channels Primes Cell Death in Transient Forebrain Ischemia"
Publishing in Neuron, Volume 43, Number 1, July 8, 2004, pages 43-55.