To evaluate the effects of disruption of cerebellar cortical output during the critical period of cerebellar expansion in the mouse.

Cerebellar pathology in early pre-term infants as well as acquired lesions of the cerebellum in clinical entities requiring resection of posterior fossa tumors heavily implicate the cerebellum in a wide range of neurodevelopmental disability beyond motor control. However, the manner in which the timing of cerebellar insult differentially contributes to behavioral outcomes is not currently characterized. Understanding how cerebellar disruptions differentially effect developmental outcomes will contribute significantly to the mechanistic understanding of cerebellar influence on cortical function.

We have developed and validated an inducible cre/lox mediated mouse line (L7-tTA; Tet-O-Cre; VGAT ^flox/flox) that allows for deletion of the vesicular GABA transporter in the Purkinje cell population with removal of doxycycline from the diet. We mice from doxycycline enriched feed at postnatal day 0 (P0) and P20. Subsequently we assay behavior at 6-8 weeks of age.

We find that early disruption of Purkinje cell output via inducible deletion of VGAT leads to pervasive developmental phenotypes including a significant gross motor phenotype that persists across training on the rotarod assay. However, in mice in which VGAT was deleted at P20, there is only a mild early deficit in the rotarod assay which resolves over the course of the training. On the other hand, in the P20 mice, there is significant deficits in innate stereotyped behavior (marble burying) and hypermotor behavior in open field assays.