Purkinje Cell-Specific Knockout of the Protein Phosphatase PP2B Impairs Potentiation and Cerebellar Motor Learning

Abstract

SUMMARY Cerebellar motor learning is required to obtain procedural skills. Studies have provided supportive evidence for a potential role of kinase-mediated long-term depression (LTD) at the parallel fiber to Purkinje cell synapse in cerebellar learning. Recently, phosphatases have been implicated in the induction of potentiation of Purkinje cell activities in vitro, but it remains to be shown whether and how phosphatase-mediated potentiation contributes to motor learning. Here, we investigated its possible role by creating and testing a Purkinje cell-specific knockout of calcium/calmodulin-activated protein-phosphatase-2B (L7-PP2B). The selective deletion of PP2B indeed abolished postsynaptic long-term potentiation in Purkinje cells and their ability to increase their excitability, whereas LTD was unaffected. The mutants showed impaired “gain-decrease” and “gain-increase” adaptation of their vestibulo-ocular reflex (VOR) as well as impaired acquisition of classical delay conditioning of their eyeblink response. Thus, our data indicate that PP2B may indeed mediate potentiation in Purkinje cells and contribute prominently to cerebellar motor learning.

Distinct cerebellar engrams in short-term and long-term motor learning

“…The absence of LTD might be compensated by feed-forward inhibition from the ML inhibitory interneurons to PCs (28). Other contributors including long-term potentiation of PF-PC synapses might be also relevant for VOR gain increase and gain decrease (15). Additionally, many types of synaptic and intrinsic plasticity in the cerebellar cortex and its target nuclei have been suggested to contribute synergistically to motor learning in the last decade (6, 16).…”

“…However, LTD's role in motor learning has been recently questioned by a few mutant mice lines (13) and mice with pharmacological treatments (14) that showed lack of LTD but no impairment of learning. Furthermore, long-term potentiation in PF-PC synapses has been also shown to be involved in the motor learning (15). Recent evidence indicates that various forms of synaptic plasticity works synergistically and can compensate each other when one is missing in cerebellar motor learning (16).…”

Distinct kinetics of synaptic structural plasticity, memory formation, and memory decay in massed and spaced learning

“…It is believed that memory is supported by the balance between the formation and recovery processes (42). Previous studies have shown that kinases (43,44) and phosphatases (33) act as switches of synaptic plasticity, thus regulating memory formation and reversal processes (45,46). Thus, the slow formation of memory by massed training may allow strong reversal processes and induce the rapid decay of long-lasting memory, whereas the rapid formation of memory observed in spaced training may strongly suppress reversal processes.…”

“…Despite recent controversies on the role of long-term depression (LTD) and a postulated role of long-term potentiation in cerebellar motor learning (31)(32)(33), this study first showed that LTD as a form of reduced AMPARs in PF-PC synapses does occur in physiological learning.…”

Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber–Purkinje cell synapses via cannabinoid signaling

“…Purkinje cell synapses are widely considered to be a requisite for cerebellar motor learning (1)(2)(3). Neuromodulators that can shift the induction probabilities for various types of plasticity at this synapse may thus fine-tune the conditions under which motor learning can occur.…”