Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss.

Although behavioral inflexibility and Purkinje cell loss are both well established in autism, it is unknown if these phenomena are causally related. Using a mouse model, we tested the hypothesis that developmental abnormalities of the cerebellum, including Purkinje cell loss, result in behavioral inflexibility. Specifically, we made aggregation chimeras (Lc/+<-->+/+) between lurcher (Lc/+) mutant embryos and wildtype (+/+) control embryos. Lurcher mice lose 100% of their Purkinje cells postnatally, while chimeric mice lose varying numbers of Purkinje cells. We tested these mice on the acquisition and serial reversals of an operant conditional visual discrimination, a test of behavioral flexibility in rodents. During reversals 1 and 2, all groups of mice committed similar numbers of "perseverative" errors (those committed while session performance was <= 40% correct). Lurchers, however, committed a significantly greater number of "learning" errors (those committed while session performance was between 41% and 85% correct) than both controls and chimeras, and most were unable to advance past reversal 3. During reversals 3 and 4, chimeras, as a group, committed more "perseverative", but not "learning" errors than controls, although a comparison of Purkinje cell number and performance in individual mice revealed that chimeras with fewer Purkinje cells made more "learning" errors and had shorter response latencies than chimeras with more Purkinje cells. These data suggest that developmental cerebellar Purkinje cell loss may affect higher level cognitive processes which have previously been shown to be mediated by the prefrontal cortex, and are commonly deficient in autism spectrum disorders.