Researchers studying the molecular basis of long-term potentiation (LTP) have typically focused on the role of NMDA glutamate receptor, but two papers published in the June 11 issue of Science elucidate the role of the other glutamate receptor, the AMPA receptor. Roberto Malinow of Cold Spring Harbor Laboratory, New York, and colleagues demonstrate that AMPA receptors, previously thought to be present in a more or less static state in most of the synapses on glutamate-sensitive neurons, in fact move into and out of synapses as these synapses strengthen or weaken. They used a relatively new technique known as two-photon laser scanning microscopy, which allowed them to see inside the dendritic spines that form the receiving end of synapses. In order to follow the distribution of AMPA receptors, the researchers tagged one of the four molecular subunits of the AMPA receptor (called GluR1 or GluR-A) with a fluorescent protein and introduced the subunit via viral infection into CA1 neurons, where LTP is usually studied, of a hippocampal slice preparation. Upon synaptic stimulation to induce LTP, they were able to observe rapid delivery of tagged AMPA receptors into clusters in the cell membranes of dendrites, specifically into the dendrites' spines.

In the second paper, Peter Seeburg and Bert Sakmann of the Max Planck Institute in Heidelberg and colleagues from several other institutions generated mice that lacked the same subunit of AMPA receptors tagged by Malinow and colleagues. The other three AMPA subunits were present in the mice and combined to allow the receptor to function normally in synaptic transmission. However, the researchers found that LTP could not be induced in CA1 neurons (although it could be induced in other types of hippocampal neurons.) Since CA1 neurons employ a particularly high percentage of GluR-A subunits in their AMPA receptors relative to other hippocampal neurons, these results suggest that LTP in CA1 is dependant on this subunit. The other goal of this study was to examine the supposed but controversial link between hippocampal LTP and spatial learning. The mice exhibited no impairment in their ability to get through a water maze, so the researchers concluded that the lack of LTP in the CA1 neurons had no effect on spatial learning.

Together, these findings provide strong evidence of the importance of postsynaptic changes in LTP, as well as of the critical role of AMPA receptors.—Hakon Heimer

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Papers

  1. . Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science. 1999 Jun 11;284(5421):1811-6. PubMed.
  2. . Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science. 1999 Jun 11;284(5421):1805-11. PubMed.