小脳依存性長期記憶におけるNO-cGMP-PKGカスケードの下流因子G-substrateの機能解析

抄録

Cerebellum plays an important role in non-declarative memories such as motor memories. Cellular substrate for the cerebellar-dependent memory is long-term depression (LTD). NO-cGMP-PKG (cGMP-dependent protein kinase) pathway is shown to be involved in the induction of cerebellar LTD. NO absorbing reagent prevents cerebellar-dependent learning such as the adaptation of perturbed locomotion and VOR adaptation. Furthermore, each component of NO-soluble guanylate cyclase-cGMP-PKG pathway has been shown to be essential for the induction of LTD. However, the downstream component of PKG was not identified. Recently we molecularly cloned and characterized G-substrate, localized specifically in cerebellar Purkinje cells, as a downstream component of PKG. Further, we have generated a mice lacking G-substrate gene. Homozygous mice are vital as expected from the restricted localization of G-substrate. The behavioral analyses were conducted on the G-substrate gene knockout mice. Significant difference was not observed between the control and G-substrate knockout mice in general behaviors. However, a specific impairment was observed in long-term horizontal optokinetic response (HOKR), a cerebellar-dependent memory, without any impairment in short-term HOKR. In addition, we observed G-substrate, with shuttles between nuclear and cytosol of Purkinje cells. G-substrate may have a role in transcription and translation in the nuclear that is essential for the long-term memory. [J Physiol Sci. 2006;56 Suppl:S52]