H2-Kb and H2-Db regulate cerebellar long-term depression and limit motor learning

There are more than 50 class I MHC (MHCI) molecules in the mouse genome, some of which are now known to be expressed in neurons; however, the role of classical MHCI molecules in synaptic plasticity is unknown. We report that the classical MHCI molecules, H2-K-b and H2-D-b, are co-expressed by Purkinje cells (PCs). In the cerebellum of mice deficient for both H2-K-b and H2-D-b ((KDb-/-)-D-b), there is a lower threshold for induction of long-term depression (LTD) at parallel fiber to PC synapses. This change may be a result of additional glutamate release observed at (KDb-/-)-D-b CF to PC synapses, which are thought to train the cerebellar circuit. A behavioral correlate of cerebellar LTD is motor learning; acquisition and retention of a Rotarod behavioral task is significantly better in (KDb-/-)-D-b mice than in WT cohorts. These physiological and behavioral phenotypes in (KDb-/-)-D-b mice reveal a surprising role for classical MHCI molecules in synaptic plasticity and motor learning.