| Information storage in the mammalian brain has long been thought to occur by means of modulating the strength of excitatory synaptic connections between neurons. Glutamatergic synapses are highly specialized points of contact between neurons that are richly arrayed with proteins on the presynaptic side, where glutamate-containing vesicles fuse with the plasma membrane, and on the postsynaptic side, where AMPA receptors mediate the majority of fast excitatory transmission. Since the discovery of long-term synaptic potentiation in the hippocampus in the 1970s, a number of studies have shown that the trafficking of AMPA receptors into and out of the postsynaptic membrane plays a key role in regulating the strength of glutamatergic transmission. In the cerebellum, postsynaptic AMPA receptor removal underlies a form of long-lasting synaptic depression at the parallel fiber-Purkinje cell synapse commonly known as "cerebellar LTD." This form of synaptic plasticity is widely believed to comprise a major portion of the engram for certain types of motor learning. Since PKC activation has been shown to be critical for the induction of cerebellar LTD, we have conducted a series of studies focusing on the regulation of an AMPA receptor subunit that contains a PKC phosphorylation site within its C-terminus, namely GluR2. Through an extensive series of genetic, biochemical, immunohistochemical, and electrophysiological experiments, we show that cerebellar LTD requires GluR2 phosphorylation as well as binding of an interacting protein, PICK L Together, our studies provide the molecular backdrop for future examination of the link between cerebellar LTD and motor learning. |
