NMDARs in granule cells contribute to parallel fiber–Purkinje cell synaptic plasticity and motor learning

Abstract

Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic N-methyl-D-aspartate receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers NO signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at parallel fiber-PC (PF-PC) synapses. Consistent with this finding, the selective deletion of GC NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.

The calcium sensor, rather than the route of calcium entry, defines cerebellar plasticity pathways

“…NMDARs are postsynaptically expressed at climbing fiber (CF) synapses ( 2 ). Challenging our findings that these postsynaptic receptors promote PF-LTD ( 3 ), the authors state “NMDARs in PCs are neither involved in PF-PC synaptic plasticity nor required for cerebellar motor learning” ( 1 ). We respectfully reject this conclusion.…”

“…Schonewille et al. ( 1 ) show that genetic deletion of GluN1 N -methyl-D-aspartate receptors (NMDARs) from cerebellar granule cells (GC-GluN1 ko), but not from Purkinje cells (PC-GluN1 ko), impairs long-term depression (LTD) at parallel fiber (PF) to PC synapses and vestibuloocular reflex (VOR) phase reversal. NMDARs are postsynaptically expressed at climbing fiber (CF) synapses ( 2 ).…”

“…For LTD, an older-generation protocol was used, in which PF bursts are paired with 400-Hz CF bursts ( 1 ). We recently assessed LTD outcomes when recordings are performed in a physiological ionic milieu ([Ca 2+ ] o = 1.2 mM; [Mg 2+ ] o = 1 mM; ref.…”

“…We believe that this is the effect seen in ref. 1 . A similar debate took place >30 y ago regarding NMDARs in hippocampal long-term potentiation (LTP).…”

“…Finally, it is unclear why the authors chose VOR adaptation as a motor learning test ( 1 ), which, in their view, does not involve LTD but involves LTP ( 10 ). This is an inappropriate selection to assess the role of NMDARs in LTD.…”