Cerebellar abnormalities in the autistic brain were first reported in the late 1980s but have remained largely unexplored from a mechanistic standpoint. This symposium links recent systems, cellular and molecular approaches which have rekindled interest. As a group, we will explore how structural and functional differences in the cerebellum contribute to the etiology and specific symptoms of autism spectrum disorder, and more importantly how these may be reversed. A functional topography has recently emerged in the human cerebellum: different regions process different types of information based on the connectivity of specific areas of the cerebellum with sensorimotor, cognitive and affective processing regions of the cerebral cortex. These findings offer a new theoretical framework within which we can examine the potential role of the cerebellum in autism. Human imaging of autistic individuals in comparison with children with cerebellar damage due to tumor removal studies will be presented. In parallel, Lurcher mutant mouse chimeras, with varying numbers of Purkinje cell loss in a time-frame that is equivalent to the last trimester in humans, have been tested for stereotypy, attention, spatial memory, and behavioral inflexibility. These will be considered in terms of the disconnection that occurs between the cerebellum and forebrain structures like the prefrontal cortex. Based upon the embryology, development, inputs, connectivity, and emerging insights into function, the cerebellum stands at the cross-roads of integration of sensory input, cognitive processing, and motor output. All three of these systems are perturbed in autism suggesting an important involvement of the cerebellum in the etiology. Yet, the pathogenesis of autism remains poorly understood, and contribution of cerebellar dysfunction to these disorders is unclear. A comprehensive time-series analysis of the genome-wide RNAs expressed every 24-hours in the mouse cerebellum from embryonic day 11 through birth and thereafter provide powerful bioinformatic tools. For instance, a gene regulation network can be built where Neuroligin, a synaptic adhesion molecule, is a key factor. Neuroligin-3 knock-out mice exhibit disrupted hetero-synaptic competition, ectopic climbing fiber synapse formation, and perturbed metabotropic glutamate receptor- dependent synaptic plasticity (mGluR-LTD). These phenotypes could be rescued by re-expression of neuroligin-3 in juvenile mice, highlighting the possibility for reverting neuronal circuit alterations in autism after completion of development. Specific wiring defects in cerebellar circuits reveal an unexpected convergence of synaptic patho- physiology in this non-syndromic form of autism with those in Fragile X syndrome. Tuberous sclerosis complex (TSC) provides another ideal model of syndromic autism. It is caused by mutations in either of the TSC1/2 genes upstream of mammalian target of rapamycin (mTOR), whose excessive activation is believed to be pathogenic. Novel roles for Tsc1 in Purkinje cell function now define, for the first time, a molecular basis for investigating the cerebellar contribution to cognitive disorders such as autism. Importantly, treatment of mutants with mTOR inhibitor, rapamycin, starting in early development prevents both pathological and behavioral deficits. The reversibility of both syndromic and non-syndromic mouse models offers potential treatment options for core symptoms of autism, as well as novel insight into cerebellar contributions to cognition.