Defining the role of cerebellar Purkinje cells in autism spectrum disorders

Abstract

Understanding the contribution of cerebellar dysfunction to complex neurological diseases such as autism spectrum disorders (ASD) is an ongoing topic of investigation. In a recent paper, Tsai et al. (Nature 488:647-651, 2012) used a powerful combination of conditional mouse genetics, electrophysiology, behavioral tests, and pharmacological manipulations to address the role of Tuberous sclerosis complex 1 (Tsc1) in Purkinje cells and cerebellar function. The authors make the staggering discovery that morphological and electrophysiological defects in Purkinje cells are linked to system-wide ASD-like behavioral deficits. In this journal club, I discuss the major findings of this paper and critically assess the implications of this seminal work.

Fig. 1

Schematic overview of the cerebellar and behavioral phenotypes in control, L7;Tsc1^fl/+, L7;Tsc1^flox/flox and L7;Tsc1^flox/flox treated with rapamycin. In control, adult Purkinje cells are organized in a tightly packed monolayer. Heterozygous loss of Tsc1 results in increased Purkinje cell spine density, defects in excitability, abnormal social and repetitive behavior, and altered communication in the pups. Complete loss of Tsc1 causes an increase in the size of Purkinje cell soma and cell death (gray cells). These morphological defects are associated with reduced Purkinje cell excitability, social deficits, impaired cognitive behavior and abnormal vocalizations. However, when L7;Tsc1^flox/flox mutants are treated with rapamycin (RAPA) starting at P7, the Purkinje cell deficits are rescued (soma size and cell number), as well as social and cognitive behavior.