NR2A subunit of the N-methyl d-aspartate receptors are required for potentiation at the mossy fiber to granule cell synapse and vestibulo-cerebellar motor learning

Abstract

Traditionally studies aimed at elucidating the molecular mechanisms underlying cerebellar motor learning have been focused on plasticity at the parallel fiber to Purkinje cell synapse. In recent years, however, the concept is emerging that formation and storage of memories are both distributed over multiple types of synapses at different sites. Here, we examined the potential role of potentiation at the mossy fiber to granule cell synapse, which occurs upstream to plasticity in Purkinje cells. We show that null-mutants of N-methyl d-aspartate-NR2A receptors (NMDA-NR2A(-/-) mice) have impaired induction of postsynaptic long-term potentiation (LTP) at the mossy fiber terminals and a reduced ability to raise the granule cell synaptic excitation, while the basic excitatory output of the mossy fibers is unaffected. In addition, we demonstrate that these NR2A(-/-) mutants as well as mutants in which the C terminal in the NR2A subunit is selectively truncated (NR2A(ΔC/ΔC) mice) have deficits in phase reversal adaptation of their vestibulo-ocular reflex (VOR), while their basic eye movement performance is similar to that of wild type littermates. These results indicate that NMDA-NR2A mediated potentiation at the mossy fiber to granule cell synapse is not required for basic motor performance, and they raise the possibility that it may contribute to some forms of vestibulo-cerebellar memory formation.

BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation

“…Involvement of GluN2A-containing NMDA (GluN2A-NMDA) receptor in the development of LTP is supported by the findings that pharmacological inhibition of GluN2A by NVP-AAM077 blocks the induction of LTP in multiple brain regions including the hippocampus (Bartlett et al, 2007;Fox et al, 2006;Jin and Feig, 2010;Li et al, 2007;Liu et al, 2004;Volianskis et al, 2013), the cortex (Massey et al, 2004) as well as the amygdala (Dalton et al, 2012;Muller et al, 2009) and the nucleus accumbens (Schotanus and Chergui, 2008). Deletion of GluN2A subunit in mice results in a impaired induction of postsynaptic LTP in the dentate gyrus (Kannangara et al, 2014) and the visual cortex (Philpot et al, 2007), and at the mossy fiber to granule cell synapse in the cerebellum (Andreescu et al, 2011). On the other hand, the GluN2A-NMDA receptor is required for the glycine-evoked membrane insertion of new AMPA (a-amino-3-hydroxy-5-methy-4-isoxazole propionate) receptors (AMPARs) as well as the induction of LTP in the rat visual cortex (Li and Wang, 2013), and synaptic GluN2A-NMDA receptors are more likely to mediate the transiently increased phosphorylation of AMPAR GluA1 subunit at serine site S831 by bath application of NMDA to hippocampal slices from rats (Ai et al, 2011).…”

Signals and Learning Rules Guiding Oculomotor Plasticity

“…There have been no previous hypotheses about the signals controlling the induction of learned changes in the phase of the VOR, although previous studies have demonstrated that the phase as well as the gain of the VOR can be modified by learning (Shelhamer et al, 1994;Kramer et al, 1995;Katoh et al, 2007Katoh et al, , 2008Andreescu et al, 2011). Therefore, we evaluated whether VOR phase learning may be controlled by the candidate instructive signals we measured.…”

Cerebellar Granule Cell

“…In NR2A-C DC/DC mice, NMDA receptor opening probability is reduced and the threshold for mossy fiber-granule cell LTP induction is increased . Likewise, a marked impairment in mossy fiber-granule cell LTP induction is observed in the vestibule cerebellum of NR2A KO mice (NR2A 0/0 ) in association with a loss of consolidation of vestibule-ocular reflex (VOR) adaptation (Andreescu et al 2011). Since NMDA receptors in the cerebellum are by far more abundantly expressed in granule cells, these results suggest that NMDA receptordependent LTP at the mossy fiber-granule cell synapse is important for cerebellar learning of sensory-motor adaptation.…”

“…It seems particularly interesting to generate mice with KO of NR2A NMDA receptors subunits, since this KO can eliminate LTP at the mossy fiber-granule cell synapse (Andreescu et al 2011).…”