Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Abstract

Key points NMDA receptors (NMDARs) are required for long‐term depression (LTD) at parallel fibre–Purkinje cell synapses, but their cellular localization and physiological functions in vivo are unclear. NMDARs in molecular‐layer interneurons (MLIs), but not granule cells or Purkinje cells, are required for LTD, but not long‐term potentiation induced by low‐frequency stimulation of parallel fibres. Nitric oxide produced by NMDAR activation in MLIs probably mediates LTD induction. NMDARs in granule cells or Purkinje cells are dispensable for motor learning during adaptation of horizontal optokinetic responses. Abstract Long‐term potentiation (LTP) and depression (LTD), which serve as cellular synaptic plasticity models for learning and memory, are crucially regulated by N‐methyl‐d‐aspartate receptors (NMDARs) in various brain regions. In the cerebellum, LTP and LTD at parallel fibre (PF)–Purkinje cell (PC) synapses are thought to mediate certain forms of motor learning. However, while NMDARs are essential for LTD in vitro, their cellular localization remains controversial. In addition, whether and how NMDARs mediate motor learning in vivo remains unclear. Here, we examined the contribution of NMDARs expressed in granule cells (GCs), PCs and molecular‐layer interneurons (MLIs) to LTD/LTP and motor learning by generating GC‐, PC‐ and MLI/PC‐specific knockouts of Grin1, a gene encoding an obligatory GluN1 subunit of NMDARs. While robust LTD and LTP were induced at PF–PC synapses in GC‐ and PC‐specific Grin1 (GC‐Grin1 and PC‐Grin1, respectively) conditional knockout (cKO) mice, only LTD was impaired in MLI/PC‐specific Grin1 (MLI/PC‐Grin1) cKO mice. Application of diethylamine nitric oxide (NO) sodium, a potent NO donor, to the cerebellar slices restored LTD in MLI/PC‐Grin1 cKO mice, suggesting that NO is probably downstream to NMDARs. Furthermore, the adaptation of horizontal optokinetic responses (hOKR), a cerebellar motor learning task, was normally observed in GC‐Grin1 cKO and PC‐Grin1 cKO mice, but not in MLI/PC‐Grin1 cKO mice. These results indicate that it is the NMDARs expressed in MLIs, but not in PCs or GCs, that play important roles in LTD in vitro and motor learning in vivo.

Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias

“…In adult rodent postsynaptic PCs, NMDARs are expressed at the climbing fiber synapse, but not at the PF-PC synapse [ 65 ]. However, NMDARs at the CF-PC synapse are not required for the induction of LTD, rather NMDARs of stellate cells are necessary for LTD induction [ 66 ]. Metabotropic glutamate receptor.…”

Interneuron NMDA receptors change the gear of motor learning in the cerebellar machine

“…These results by Kono et al . () represent a major step forward to cut the Gordian knot regarding the precise subcellular localization of NMDARs in the cerebellar microcircuitry and the cellular mechanism of PF–CF signal integration. Future experiments with cell‐specific cKO of nNOS will help localize the cellular source of NO.…”

“…Exciting results using Cre–LoxP‐based cKOs as exemplified by Kono et al . () will prove invaluable in advancing our understanding of how long‐term synaptic plasticity contributes to the cerebellar motor and non‐motor functions via the engagement of interneurons to adjust the gears in the cerebellar machine (Eccles et al . ).…”

“…In this issue of The Journal of Physiology , Kono et al . () provide compelling evidence about the role of NMDARs in cerebellar LTD in vitro and motor learning in vivo by generating cell‐specific (granule cell (GC), PC, MLI/PC) conditional knock‐outs (cKOs) of the obligatory GluN1 NMDAR subunit encoded by the Grin1 gene. They confirmed by patch‐clamp recordings in brain slices that functional NMDARs can be deleted from GCs, MLIs and PCs.…”

“…Because optokinetic response adaptation was measured without the GABA A blocker that was employed for LTD in acute slices, manipulation of the activity of cerebellar MLIs specifically expressing excitatory or inhibitory channelrhodopsins in vivo (Kruse et al 2014) will further establish the distinct roles of interneuron NMDARs in motor and non-motor functions. Exciting results using Cre-LoxP-based cKOs as exemplified by Kono et al (2019) will prove invaluable in advancing our understanding of how long-term synaptic plasticity contributes to the cerebellar motor and non-motor functions via the engagement of interneurons to adjust the gears in the cerebellar machine (Eccles et al 1967).…”