When the B-team runs plasticity: GluR2 receptor trafficking in cerebellar long-term potentiation

Abstract

Common wisdom among neuroscientists holds that cerebellar learning and synaptic plasticity are “somehow” different from their counterparts in other brain areas. This notion is largely based on the assumption that forms of cerebellar motor learning are mediated by long-term depression (LTD) of synaptic transmission at parallel fiber (PF)–Purkinje cell (PC) synapses, whereas in other brain areas, such as the hippocampus, long-term potentiation (LTP) is seen as the cellular learning correlate. But what distinguishes cerebellar synaptic plasticity mechanisms from those at other types of synapses, for example, at the well characterized hippocampal CA3–CA1 synapse? In a recent issue of PNAS, Kakegawa and Yuzaki (1) demonstrate that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor delivery into synapses is involved in a recently discovered form of cerebellar LTP, enabling comparison with similar processes at hippocampal CA3–CA1 synapses. At these glutamatergic synapses, fast excitation relies on AMPA receptors, which are heteromeric complexes of the four homologous subunits GluR1 to GluR4 (also GluRA to GluRD). In hippocampal pyramidal cells, the majority of AMPA receptors consist of GluR1–GluR2 and GluR2–GluR3 heteromeric complexes. The current understanding is that hippocampal plasticity largely rests on modifications of the GluR1 subunit, resulting in altered GluR1 subunit trafficking and/or single-channel conductance changes. Kakegawa and Yuzaki (1) present evidence that plasticity at cerebellar PF–PC synapses differs substantially from hippocampal plasticity and relies on GluR2 subunit trafficking. Their data provide an example of a form of LTP that depends on the activity-dependent insertion of GluR2 subunits into synapses. These findings complement an emerging picture of remarkable differences between hippocampal and cerebellar plasticity, but also astonishing similarities. In several aspects, cerebellar plasticity provides a mirror image of hippocampal plasticity: hippocampal LTP induction requires large calcium transients that promote the activation of calcium/calmodulin-dependent kinase II …