Claire Piochon et al.; PNAS February 22, 2022 119 (8) e2119598119

Figure: Postsynaptic NMDA receptors promote cerebellar LTD.

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). 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.

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 ([Ca²⁺]_o = 1.2 mM; [Mg²⁺]_o = 1 mM; ref. 4) and observed that LTD does not result from PF burst pairing with single complex spikes, even when 400-Hz CF stimulation is used (5). Instead, LTD requires complex spike firing in naturally occurring clusters, a prolonged pattern favoring activation of the critical calcium sensor CaMKII (5⇓–7). It remains to be determined whether or not LTD observed under these realistic conditions depends on postsynaptic NMDARs.

See: https://www.pnas.org/content/119/8/e2119598119