Purkinje Cell-Specific Knockout of the Protein Phosphatase PP2B Impairs Potentiation and Cerebellar Motor Learning (original) (raw)
Related papers
F1000 - Post-publication peer review of the biomedical literature, 2000
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/calmodulinactivated 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.
A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005
Cerebellar parallel fiber (PF)-Purkinje cell (PC) synapses can undergo postsynaptically expressed long-term depression (LTD) or long-term potentiation (LTP). PF-LTD induction requires the coactivity of the PF and CF (climbing fiber) inputs to PCs and a concomitant calcium transient and activation of protein kinase C (PKC). PF-LTP can be induced by PF activity alone and requires a lower calcium transient for its induction than PF-LTD. The cellular events triggering PF-LTP induction are not well characterized. At other types of synapses (e.g., in the hippocampus), bidirectional synaptic plasticity is under control of a kinase/phosphatase switch, with PKC and CaMKII (calcium/calmodulin-dependent kinase II) activity promoting LTP induction and phosphatase activity promoting LTD induction. Here, we have tested for the involvement of protein phosphatase 1 (PP1), PP2A, and PP2B (calcineurin) in cerebellar LTP induction using whole-cell patch-clamp recordings in rat cerebellar slices. LTP i...
European Journal of Neuroscience, 2007
Although protein-tyrosine phosphorylation is important for hippocampus-dependent learning, its role in cerebellum-dependent learning remains unclear. We previously found that PTPMEG, a cytoplasmic protein-tyrosine phosphatase expressed in Purkinje cells (PCs), bound to the carboxyl-terminus of the glutamate receptor d2 via the postsynaptic density-95 ⁄ discs-large ⁄ ZO-1 domain of PTPMEG. In the present study, we generated PTPMEG-knockout (KO) mice, and addressed whether PTPMEG is involved in cerebellar plasticity and cerebellum-dependent learning. The structure of the cerebellum in PTPMEG-KO mice appeared grossly normal. However, we found that PTPMEG-KO mice showed severe impairment in the accelerated rotarod test. These mice also exhibited impairment in rapid acquisition of the cerebellum-dependent delay eyeblink conditioning, in which conditioned stimulus (450-ms tone) and unconditioned stimulus (100-ms periorbital electrical shock) were co-terminated. Moreover, long-term depression at parallel fiber-PC synapses was significantly attenuated in these mice. Developmental elimination of surplus climbing fibers and the physiological properties of excitatory synaptic inputs to PCs appeared normal in PTPMEG-KO mice. These results suggest that tyrosine dephosphorylation events regulated by PTPMEG are important for both motor learning and cerebellar synaptic plasticity.
The Journal of Cell Biology, 2003
he molecular basis for cerebellar plasticity and motor learning remains controversial. Cerebellar Purkinje cells (PCs) contain a high concentration of cGMPdependent protein kinase type I (cGKI). To investigate the function of cGKI in long-term depression (LTD) and cerebellar learning, we have generated conditional knockout mice lacking cGKI selectively in PCs. These cGKI mutants had a normal cerebellar morphology and intact synaptic T calcium signaling, but strongly reduced LTD. Interestingly, no defects in general behavior and motor performance could be detected in the LTD-deficient mice, but the mutants exhibited an impaired adaptation of the vestibulo-ocular reflex (VOR). These results indicate that cGKI in PCs is dispensable for general motor coordination, but that it is required for cerebellar LTD and specific forms of motor learning, namely the adaptation of the VOR.
Cerebellar Purkinje cell activity drives motor learning
Nature Neuroscience, 2013
volume 16 | number 12 | December 2013 nature neuroscience b r i e f co m m u n i c at i o n s in the cerebellar flocculus reflects both the vestibular stimulus and the direction of the visual stimulus (the eye movements made to track the visual stimulus); thus, these neurons carry the information required to control the direction of learning 6,13 . We tested whether learned changes in the VOR could be induced by pairing a vestibular stimulus with direct activation of Purkinje cells in the absence of any visual stimulus.
Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning
Nature …, 2009
Although feed-forward inhibition onto Purkinje cells was first documented forty years ago, we still understand little of how inhibitory interneurons contribute to cerebellar function in behaving animals. Using a mouse line (PC-Δγ2) in which GABAA receptor-mediated synaptic inhibition was selectively removed from Purkinje cells, we examined how feed-forward inhibition from molecular layer interneurons regulates adaptation of the vestibulo-ocular reflex. Whereas impairment of baseline motor performance was relatively mild, the ability to adapt the phase of the vestibulo-ocular reflex and to consolidate gain adaptations, was strongly compromised. Purkinje cells showed abnormal patterns of simple spikes, both during and in the absence of evoked compensatory eye movements. Based on modeling of the experimental data, we propose that feed-forward inhibition, by controlling the fine scale patterns of Purkinje cell activity, enables the induction of plasticity in neurons of the cerebellar and vestibular nuclei.
Journal of Neurochemistry, 2014
Read the full article 'Cdk5/p35 is required for motor coordination and cerebellar plasticity' on page 53. Abbreviations used: AMPAR, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor; CaMKII, Ca 2+ /calmodulin-dependent protein kinase; Cdk5, cyclin-dependent kinase 5; CF, climbing fibre; EPSC, excitatory post-synaptic current; GC, granule cell; GluN2, NMDA receptor subunit; IP3R1, inositol 1,4,5-trisphosphate receptor type 1; LTD, long-term depression; LTP, long-term potentiation; MF, mossy fibre; NMDAR, N-methyl-D-aspartate-type ionotropic glutamate receptor; p35, neuron-specific activator subunit of Cdk5; PC, Purkinje cell; PF, parallel fibre; PSD-95, post-synaptic density protein 95; STEP, striatal-enriched tyrosine phosphatase; VDCC, voltage-dependent Ca 2+ channel.
Proceedings of the National Academy of Sciences, 2004
tial component of cerebellar long-term depression (LTD), a form of synaptic plasticity involved in motor learning. Here, we report that protein phosphatase 2A (PP-2A) plays a specific role in controlling synaptic strength and clustering of AMPARs at synapses between granule cells and Purkinje cells. In 22-to 35-day cerebellar cultures, specific inhibition of postsynaptic PP-2A by fostriecin (100 nM) or cytostatin (10 -60 M) induced a gradual and use-dependent decrease of synaptic current evoked by the stimulation of a single granule cell, without altering receptor kinetics nor passive electrical properties. By contrast, PP-2A inhibition had no effect on immature Purkinje
PLoS ONE, 2010
Background: Long-term potentiation (LTP) at the parallel fibre-Purkinje cell synapse in the cerebellum is a recently described and poorly characterized form of synaptic plasticity. The induction mechanism for LTP at this synapse is considered reciprocal to ''classical'' LTP at hippocampal CA1 pyramidal neurons: kinases promote increased trafficking of AMPA receptors into the postsynaptic density in the hippocampus, whereas phosphatases decrease internalization of AMPA receptors in the cerebellum. In the hippocampus, LTP occurs in overlapping phases, with the transition from early to late phases requiring the consolidation of initial induction processes by structural re-arrangements at the synapse. Many signalling pathways have been implicated in this process, including PI3 kinases and Rho GTPases.
The Journal of Neuroscience, 2001
A longstanding but still controversial hypothesis is that longterm depression (LTD) of parallel fiber-Purkinje cell synapses in the cerebellum embodies part of the neuronal information storage required for associative motor learning. Transgenic mice in which LTD is blocked by Purkinje cell-specific inhibition of protein kinase C (PKC) (L7-PKCI mutants) do indeed show impaired adaptation of their vestibulo-ocular reflex, whereas the dynamics of their eye movement performance are unaffected. However, because L7-PKCI mutants have a persistent multiple climbing fiber innervation at least until 35 d of age and because the baseline discharge of the Purkinje cells in the L7-PKCI mutants is unknown, factors other than a blockage of LTD induction itself may underlie their impaired motor learning. We therefore investigated the spontaneous discharge of Purkinje cells in alert adult L7-PKCI mice as well as their multiple climbing fiber innervation beyond the age of 3 months. We found that the simple spike and complex spike-firing properties (such as mean firing rate, interspike interval, and spike count variability), oscillations, and climbing fiber pause in the L7-PKCI mutants were indistinguishable from those in their wild-type littermates. In addition, we found that multiple climbing fiber innervation does not occur in cerebellar slices obtained from 3to 6-month-old mutants. These data indicate (1) that neither PKC inhibition nor the subsequent blockage of LTD induction disturbs the spontaneous discharge of Purkinje cells in alert mice, (2) that Purkinje cell-specific inhibition of PKC detains rather than prevents the developmental conversion from multiple to mono-innervation of Purkinje cells by climbing fibers, and (3) that as a consequence the impaired motor learning as observed in older adult L7-PKCI mutants cannot be attributable either to a disturbance in the baseline simple spike and complex spike activities of their Purkinje cells or to a persistent multiple climbing fiber innervation. We conclude that cerebellar LTD is probably one of the major mechanisms underlying motor learning, but that deficits in LTD induction and motor learning as observed in the L7-PKCI mutants may only be reflected in differences of the Purkinje cell signals during and/or directly after training.