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Modulation of AMPA receptor trafficking and its involvement in synaptic plasticity and spatial memory

University of British Columbia

The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors mediates the fast excitatory synaptic transmission in the mammalian brain. Increasing evidence suggests that rapid movement of AMPARs into and out of synapses is the major mechanism for changes in synaptic strength, which is thought to underlie learning and memory. Although the bidirectional hippocampal synaptic plasticity, particularly long-term potentiation (LTP) and long-term depression (LTD), has been regarded as a candidate mechanism for long-term spatial memory (LSM), the precise contribution of LTP and LTD to LSM remains poorly understood. Using antagonists that target NMDARs carrying specific NR2 subunits, we found that LTP and LTD in freely moving rats can be selectively abolished by NR2A and NR2B antagonists, respectively. Using the Morris water maze, we found that only the NR2B antagonist disturbed the consolidation of LSM. In addition, a similar LSM deficit was observed when the expression of LTD was prevented by inhibiting regulated AMPAR endocytosis. Thus, these findings support a functional requirement of hippocampal LTD in the consolidation of LSM. Blocking LTP by NR2A-preferential antagonist had no effects on LSM. However, another structurally and mechanistically different LTP-specific inhibitor is still lacking. Since the expression of LTP is thought to be mediated by the facilitated exocytosis of AMPARs, we therefore attempted to identify novel AMPAR binding partner(s) using co-immunoprecipitatoin with anti-GluR1 or anti-GluR2 antibody followed by mass spectrometric analysis. We found that p97, also called valosin-containing protein (VCP), specifically interacts with and modulates trafficking of homomeric GluR1 receptors. Using various truncated and deleted constructs of GluR1, we found that p97 interacts with N-terminal of GluR1, but not GluR2, resulting in facilitated formation of homomeric GluR1 receptors by decreasing GluR1/GluR2 heteromeric receptors formation. Moreover, we found that under basal conditions, p97 retained homomeric GluR1 AMPARs in the intracellular pool, but immediately after the induction of LTP, it disassociated from GluR1 and hence, allowed these homomeric AMPARs insert into the postsynaptic membrane, thereby contributing to LTP expression. Thus, our results highlight a previously unknown molecular mechanism by which p97 regulates formation and trafficking of homomeric GluR1 AMPARs, and thereby plays a critical role in LTP expression.

Text

2010-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/23345

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/