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

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.

Dual involvement of G-substrate in motor learning revealed by gene deletion

“…Together, these results consistently support the current view that LTD is an essential mechanism of cerebellum-dependent learning. In this context, a close association was also reported very recently in mice lacking delphilin in Purkinje cells, whose LTD induction and OKR adaptation were both enhanced (43). Temporary diminution of LTD, which is now shown to be associated with attenuation of short-term OKR adaptation in G-substrate knockout mice, may also impair other forms of motor learning such as motor coordination on the rotor rod and eyeblink conditioning.…”

A nucleator arms race: cellular control of actin assembly

“…Different delphilin splice variants contain a palmitoylation site and PDZ domains, sequences that likely influence its ability to associate with cellular membranes142,143. Consistent with a role in neuronal function, mice lacking delphilin have altered synaptic plasticity144.…”

Lipid signaling in cytosolic phospholipase A 2 α–cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning

“…Whether LTD actually underlies motor learning is a matter of discussion. In a number of knockout mutants tested so far, the loss of LTD detected in slice conditions parallels a disturbance in motor learning (21), or, in a certain case, enhanced LTD parallels an enhanced motor learning (46). However, in a fragile-X mental retardation mouse model, enhanced LTD accompanies impaired motor learning (47).…”