Wednesday, August 22, 2007

Calcium-permeable AMPA receptors   posted by amnestic @ 8/22/2007 01:55:00 PM

AMPA receptors are the major receptors for excitatory neurotransmission. There is a firm basis for the hypothesis that synaptic plasticity and thus memory is based on the increase or decrease in the number of AMPA receptors in specific synapses. AMPA receptors are actually ligand-activated ion channels made up of subunits. Sodium passing through the AMPA channel depolarizes the membrane potential of the receiving neuron and pushes the cell toward firing. Calcium can also pass through AMPA channels, but there is one subunit, the GluR2 subunit, that can block calcium. AMPA receptors lacking GluR2 are relatively rare, so most AMPA receptors can't pass calcium.

Calcium has implications beyond membrane potential changes because calcium acts as a signaling molecule activating enzymes downstream. Plant et al published a report last year showing that GluR2-lacking AMPA receptors are incorporated into synapses for about 25 minutes after induction of plasticity at a synapse, after which they are replaced by GluR2-containing AMPA receptors. They were able to perform these experiments by checking the sensitivity of plasticity to a drug that should only affect GluR2-lacking AMPA receptors. This is an interesting idea because it allows for an increase in calcium signaling at specific synapses that outlasts the inducing event. This calcium signaling could serve as a mark to show the slower synapse-building machinery to find the favored synapses and get to work.

However, all is not well because Adesnik and Nicoll published pretty much the opposite result in April. I mean both labs used phillanthotoxin, the special GluR2 drug, and one got an effect and one didn't. I don't know why, but controversy is so exciting, right? John Isaac wrote a response to the Adesnik and Nicoll paper defending the Plant et al findings, but it doesn't really offer a concrete explanation for the differences. Anyone who can explain it to me gets a free hug if I ever see you.

Now, even more recently, Gray et al (TJ O'Dell's lab) seconded Adesnik and Nicoll's motion damaging the Plant/Isaac thesis. Very similar to the previous two publications but using a different drug and a different waterbath temperature, O'Dell and colleagues could find no indication that GluR2-lacking receptors were necessary for long-term plasticity. When two independent laboratories shoot down a high-profile finding, no matter how theoretically appealing, it is probably time to let it go. It is a shame that the null finding and its replication weren't published in quite as high-tier journals as the first.

Here are two recent reviews on AMPA receptors and GluR2:
Regulatory mechanisms of AMPA receptors in synaptic plasticity
The Role of the GluR2 Subunit in AMPA Receptor Function and Synaptic Plasticity
Keep an eye on the publication dates. The second review here addresses the Adesnik and Nicoll finding, but neither of them address Gray et al.

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