Protein tyrosine phosphatase receptor type R is required for Purkinje cell responsiveness in cerebellar long-term depression.

Mirthe Erkens,Jan Tg Schepens,Keiko Tanaka-Yamamoto,Wiljan Jaj Hendriks,Cynthia Prigogine,Guy Cheron,Nael Nadif Kasri,Javier Márquez-Ruiz,George J Augustine

doi:10.1186/s13041-014-0092-8

Abstract

BackgroundRegulation of synaptic connectivity, including long-term depression (LTD), allows proper tuning of cellular signalling processes within brain circuitry. In the cerebellum, a key centre for motor coordination, a positive feedback loop that includes mitogen-activated protein kinases (MAPKs) is required for proper temporal control of LTD at cerebellar Purkinje cell synapses. Here we report that the tyrosine-specific MAPK-phosphatase PTPRR plays a role in coordinating the activity of this regulatory loop.ResultsLTD in the cerebellum of Ptprr−/− mice is strongly impeded, in vitro and in vivo. Comparison of basal phospho-MAPK levels between wild-type and PTPRR deficient cerebellar slices revealed increased levels in mutants. This high basal phospho-MAPK level attenuated further increases in phospho-MAPK during chemical induction of LTD, essentially disrupting the positive feedback loop and preventing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation and endocytosis.ConclusionsOur findings indicate an important role for PTPRR in maintaining low basal MAPK activity in Purkinje cells. This creates an optimal ‘window’ to boost MAPK activity following signals that induce LTD, which can then propagate through feed-forward signals to cause AMPAR internalization and LTD.

Highlights

Regulation of synaptic connectivity, including long-term depression (LTD), allows proper tuning of cellular signalling processes within brain circuitry
The reduction of Parallel fiber (PF)-Excitatory postsynaptic current (EPSC) calculated at 30–40 min after PF&ΔV was significantly smaller in the Ptprr−/− Purkinje cell (PC) than in the wild-type PCs (wild-type: 28.3 ± 6.3% (n = 9), Ptprr−/−: 1.6 ± 7.2% (n = 9), p < 0.05, Student’s t-test)
The paired-pulse facilitation (PPF) ratios were unaltered in Ptprr−/− PCs compared with wild-type PCs (Figure 2D; p = 0.1, two-way ANOVA; n = 14 for wild type, n = 12 for Ptprr−/−), indicating that the probability of glutamate release from presynaptic PF terminals is not affected in Ptprr−/− mice

Summary

Introduction

Regulation of synaptic connectivity, including long-term depression (LTD), allows proper tuning of cellular signalling processes within brain circuitry. A key centre for motor coordination, a positive feedback loop that includes mitogen-activated protein kinases (MAPKs) is required for proper temporal control of LTD at cerebellar Purkinje cell synapses. Comparison of basal phospho-MAPK levels between wild-type and PTPRR deficient cerebellar slices revealed increased levels in mutants. This high basal phospho-MAPK level attenuated further increases in phospho-MAPK during chemical induction of LTD, essentially disrupting the positive feedback loop and preventing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation and endocytosis. One of the major mechanisms that regulate synaptic strength involves the regulated trafficking of α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptors (AMPARs) into and out of synapses.

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Results

Discussion

Conclusion