Enhancement of Both Long-Term Depression Induction and Optokinetic Response Adaptation in Mice Lacking Delphilin

Tomonori Takeuchi,Masahiro Fukaya,Kenji Sakimura,Tomoo Hirano,Tasuku Wainai,Masayoshi Mishina,Masahiko Watanabe,Takashi Yoshida,Hisashi Mori,Gen Ohtsuki,Manami Yamashita,Yoshito Yamazaki,Susumu Kawamoto

doi:10.1371/journal.pone.0002297

Abstract

In the cerebellum, Delphilin is expressed selectively in Purkinje cells (PCs) and is localized exclusively at parallel fiber (PF) synapses, where it interacts with glutamate receptor (GluR) δ2 that is essential for long-term depression (LTD), motor learning and cerebellar wiring. Delphilin ablation exerted little effect on the synaptic localization of GluRδ2. There were no detectable abnormalities in cerebellar histology, PC cytology and PC synapse formation in contrast to GluRδ2 mutant mice. However, LTD induction was facilitated at PF-PC synapses in Delphilin mutant mice. Intracellular Ca2+ required for the induction of LTD appeared to be reduced in the mutant mice, while Ca2+ influx through voltage-gated Ca2+ channels and metabotropic GluR1-mediated slow synaptic response were similar between wild-type and mutant mice. We further showed that the gain-increase adaptation of the optokinetic response (OKR) was enhanced in the mutant mice. These findings are compatible with the idea that LTD induction at PF-PC synapses is a crucial rate-limiting step in OKR gain-increase adaptation, a simple form of motor learning. As exemplified in this study, enhancing synaptic plasticity at a specific synaptic site of a neural network is a useful approach to understanding the roles of multiple plasticity mechanisms at various cerebellar synapses in motor control and learning.

Highlights

Various studies suggest the important roles of the cerebellum in the regulation of fine motor control and motor learning [1,2]
Double immunostaining for calbindin and vesicular glutamate transporter 1 (VGluT1) revealed that Purkinje cells (PCs) extended wellarborized dendrites studded with numerous spines (Fig. 1E,F), which were tightly associated with parallel fiber (PF) terminals (Fig. 1I,J)
We showed that Delphilin ablation at PF-PC synapses facilitates Long-term depression (LTD) induction at PF synapses and enhances optokinetic response (OKR) gainincrease adaptation without affecting any detectable histological abnormalities

Summary

Introduction

Various studies suggest the important roles of the cerebellum in the regulation of fine motor control and motor learning [1,2]. The wealth of knowledge of neural circuits in the cerebellum has led to the construction of models and theories of cerebellar functions [4,5,6]. These make the cerebellum an ideal system for studying the molecular and cellular mechanisms of brain function. We report that Delphilin ablation results in the enhancement of both LTD induction at PF-PC synapses and optokinetic response (OKR) gain-increase adaptation, without affecting any detectable histological abnormalities. The phenotypes of Delphilin mutant mice are consistent with the idea that LTD induction at PF-PC synapses is a crucial rate-limiting step in OKR gain-increase adaptation, a simple form of motor learning

Methods

Results

Conclusion