Introduction
Long-term potentiation of synaptic transmission is a cellular model for the changes occuring during learning and memory. The mechanisms underlying this form of activity-induced plasticity have been examined for many years. Recent evidence supports the view that a significant amount of the modification is due to delivery of AMPA sensitive glutamate receptors to synapses.
Methods
We have used a combination of techniques to address the mechanisms underlying LTP. We study hippocampal slices, either acute or cultured for 1-14 days. We measure synaptic transmission with whole-cell recordings from CA1 neurons. We deliver genes of interest into these slices with Sindbis expression system. We monitor distribution of recombinant GFP-tagged proteins using tw0-photon microscopy. We detect delivery of recombinant AMPA-sensitive receptors by expressing receptors that differ biophysically (rectification) from endogenous receptors.
Results
Using two-photon microscopy, we detect delivery of GFP-tagged AMPA receptors into dendritic spines following LTP-inducing stimuli. Using electrophysiology we detect functional delivery of AMPA receptors into synapses. By making point mutations in the cytoplasmic tail of AMPA-receptor subunits, we can show that an interaction between GluR1 and a PDZ-domain protein is critical for activity-driven delivery of AMPA receptors to synapses.
Conclusions
From our studies with recombinant receptors we arrive at a model of AMPA receptor trafficking that can account for maintenance of synaptic strength after transient changes in synaptic receptor number. This model has two means by which AMPA-Rs reach synapses: an activity-dependent delivery and an activity-independent replacement.
References
Shi S-H, Hayashi Y, Petralia R, Zaman S, Wenthold R, Svoboda K, Malinow R: Rapid Spine Delivery and Redistribution of AMPA Receptors after Synaptic NMDA Receptor Activation. Science 284:1811-1816 (1999).
Hayashi Y, Shi S, Esteban J, Piccini A, Poncer JC, and Malinow R: Driving AMPA receptors into synapses by CaMKII or LTP: Requirement of GluR1-PDZ-domain interaction. Science 287:2262-7 (2000).