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 and Purkinje cells, bidirectional plasticity is shaped by the balance between transcellular nitric oxide driven by presynaptic NMDA 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 nitric oxide (NO) signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at parallel fiber-Purkinje cell (PF-PC) synapses. Consistent with this finding, the selective deletion of granule cells NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.Significance StatementLearning depends on synaptic plasticity. The signaling mechanisms that control induction of this plasticity determines the learning rules at the specific synapse involved. Moreover, the relationship between the activity patterns of synaptic inputs and the type, direction, and level of plasticity induced may evolve during development. Here, we establish a key link between NMDA receptor activation presynaptic to cerebellar Purkinje cells, downstream signaling, and the ability of adult animals to learn a cerebellar motor task.

Plasticity mechanisms of genetically distinct Purkinje cells

“…NMDA receptors contribute significantly to the calcium signal triggered by CF activity (Figure 2). [73,74] The activation of presynaptic NMDA receptors on PFs also plays a role in the induction of both LTP and LTD. [75] NMDA receptors contribute to LTD and LTP by stimulating presynaptic nitrous oxide (NO) production. [76] NO contributes to LTD through activation of phospholipase A2 (PLA2), and the production of arachidonic acid (AA), whereas it contributes to LTP through activation of NSF (Figure 2).…”