Long-term depression (LTD) at parallel fiber to Purkinje cell (PC) synapse in the cerebellum is the cellular basis for cerebellar motor learning. Although some signaling molecules including protein kinase G (PKG) and MAP kinase (MAPK) are essential for the LTD induction, the molecular mechanism for long-term memory has not been fully understood.
8-nitro-cGMP is produced by guanylyl cyclase in the presence of nitric oxide and reactive oxygen species (ROS). In contrast to cGMP, 8-nitro-cGMP has resistance to PDE-dependent catalysis and can activate PKG for a long time. Therefore, we hypothesized that 8-nitro-cGMP-mediated signal is essential for cerebellar LTD. Application of 8-nitro-cGMPS, an analog for 8-nitro-cGMP, to PCs significantly inhibited LTD induction in acute mouse cerebellar slices. Pharmacological inhibition of ROS also abolished LTD induction, suggesting involvement of ROS/8-ntiro-cGMP signals in cerebellar LTD.
8-nitro-cGMP activates protein kinase G (PKG), and our previous studies indicate PKG activate extracellular signal related kinase (ERK), a type of MAPK. We therefore examined involvement of ERK in cerebellar LTD, using mutant mice lacking ERK 1 and/or 2. The LTD was impaired in the ERK 1&2 double-knockout cerebellum. There results indicate essential role of 8-nitro-cGMP – ERK signals in cerebellar LTD.