GluA3-Mediated Synaptic Plasticity and Dysfunction in the Cerebellum and in the Hippocampus
GluA3-gemedieerde synaptische plasticiteit en disfunctie in het cerebellum en hippocampus
The hippocampus and the cerebellum are two different brain regions that encode
different types of memories. Whilst the hippocampus deals with declarative
memory, the cerebellum is mainly involved in procedural memory.
In the cerebellum, granule cells give rise to parallel fibers, which form synaptic points with Purkinje cells - the parallel fiber-Purkinje cell synapse. We found five mutations in cerebellar granule cell that did not affect phase reversal, a type of cerebellar learning. However, in looking at Purkinje cells whose GluA3 subunit of the AMPA receptors was knocked out, we saw an impairment of phase reversal adaptation. We show, then, that the GluA3 AMPA receptor subunit is involved in crucial cerebellar motor learning. We also show that this GluA3-mediated mechanism defies some long-established rules regarding the potentiation of the parallel fiber-Purkinje cell synapse.
In the hippocampus, learning depends on the trafficking of GluA1-containing AMPARs to synapses. GluA3-containing AMPARs, however, don’t seem to contribute much to synaptic currents, synaptic plasticity or learning, though they are present. We found that, in the hippocampus, the GluA3 subunit doesn’t contribute to memory formation but does control memory retrieval. We see how the effects of knocking out GluA3 reveal that the hippocampus AMPAR-mediated rules for learning are opposite to the rules uncovered for the cerebellum regarding the GluA1 and GluA3 subunits of the AMPA receptors.
Lastly, we found that memories coded in the hippocampus are affected by amyloid-β, and that its effects occur through the removal of GluA3 from synapses. We demonstrate GluA3 subunit’s role in rendering the synapses susceptible to amyloid-β and how it requires PKCα phosphorylation of the GluA3 subunit at serine 885. We finally propose that Aβ causes synaptic deficits by corrupting the constitutive cycling of GluA3-containing AMPA-receptors at synapses.
|Keywords||AMPA Receptor, Memory, Hippocampus, Cerebellum, Alzheimer's Disease|
|Promotor||C.I. de Zeeuw (Chris) , H.W.H.G. Kessels (Helmut W.H.G) , B.H.J. Winkelman (Beerend)|
|Publisher||Erasmus University Rotterdam|
da Silva Matos, C.M. (2019, November 20). GluA3-Mediated Synaptic Plasticity and Dysfunction in the Cerebellum and in the Hippocampus. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/121451