Cerebellar LTD (long-term depression) is induced by a molecular mechanism different from hippocampal LTD. Cerebellar LTD is induced when NO increases intracellular cGMP concentration through the activation of soluble guanylate cyclase. cGMP, in turn, activates cGMP-dependent protein kinase (PKG). Each component in the cascade activating the PKG has been shown to be essential for the induction of cerebellar LTD. The cloned G-substrate is exclusively expressed in cerebellar Purkinje cells. The recombinant G-substrate was an excellent substrate for PKG and upon phosphorylation, it inhibited protein phosphatase-1 and -2A.

The cascade initiated with NO results in the phosphorylation of G-substrate in cerebellar Purkinje cells. The phospho-G-substrate may result in an enhanced phosphorylation of the proteins in the Purkinje cells by inhibiting protein phosphastases. One of the potential targets is the glutamate receptor (AMPA receptor) where decreased efficiency is reported and proposed to be the major mechanism underlying cerebellar LTD. The phosphorylation of AMPA receptor may result in desensitization and internalization of the receptor or redistribution of the receptor (see BSI News No. 5 by Dr. Hirai in Lab. for Memory and Learning) in cerebellar Purkinje cells.