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The role of AMPA receptor subunits in synaptic plasticity
- Granger, Adam John
- Advisor(s): Nicoll, Roger A
Abstract
Memories are stored in the brain via specific patterns of connectivity between individual neurons. Learning occurs through changes in this pattern of connectivity in response to activity, such that a synapse becomes more or less effective at influencing a postsynaptic neuron. This process, called synaptic plasticity, has been demonstrated at excitatory glutamatergic synapses of the hippocampus, where precise patterns of activity can either increase (long-term potentiation, LTP) or decrease (long-term depression, LTD) synaptic strength. Both LTP and LTD are carried out through changes in the number of postsynaptic AMPA-type glutamate receptors (AMPARs). Therefore, to understand synaptic plasticity, we must also understand the trafficking of AMPARs. In the case of LTP expression, the AMPAR subunit GluA1 is specifically required, and modifications of its cytoplasmic tail (C-tail) are thought to be particularly important for the activity-dependent recruitment of AMPARs. To identify the minimum region of the GluA1 C-tail required for LTP, I used a single-cell molecular replacement strategy where all endogenous AMPARs are replaced with transfected subunits. Surprisingly, I found no requirement for the GluA1 C-tail or for GluA1 generally for expression of LTP. Instead, molecular replacement with either GluA2 or the kainate receptor subunit GluK1 resulted in normal LTP. The only conditions under which LTP was impaired were those with a dramatically decreased pool of receptors on the neuronal surface. Similar to LTP, I also found no specific AMPAR subunit requirement for LTD, which was expressed normally in neurons only expressing GluK1. These results suggest that synaptic plasticity is not necessarily a direct modification of the glutamate receptors subunits themselves, but a broader change in the ability of the synapse to anchor postsynaptic receptors.
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