EXPRESSION OF A PROTEIN-KINASE-C INHIBITOR IN PURKINJE-CELLS BLOCKS CEREBELLAR LTD AND ADAPTATION OF THE VESTIBULOOCULAR REFLEX

Cerebellar long-term depression (LTD) is a model system for neuronal i nformation storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluR delta 2, glial fibrillary acidic protein) have supp orted this claim; however, this work has suffered from the limitations that the knockout technique lacks anatomical specificity and that fun ctional compensation can occur via similar gene family members. To ove rcome these limitations, a transgenic mouse (called L7-PKCI) has been produced in which the pseudosubstrate PKC inhibitor, PKC[19-31], was s electively expressed. in Purkinje cells under the control of the pcp-2 (L7) gene promoter. Cultured Purkinje cells prepared from heterozygous or homozygous L7-PKCI embryos showed a complete blockade of LTD induc tion. In addition, the compensatory eye movements of L7-PKCI mice were recorded during vestibular and visual stimulation. Whereas the absolu te gain, phase, and latency values of the vestibule-ocular reflex and optokinetic reflex of the L7-PKCI mice were normal, their ability to a dapt their vestibuloocular reflex gain during visuo-vestibular trainin g was absent. These data strongly support the hypothesis that activati on of PKC in the Purkinje cell is necessary for cerebellar LTD inducti on, and that cerebellar LTD is required for a particular form of motor learning, adaptation of the vestibule-ocular reflex.