No targeted therapies exist for the treatment of Autism Spectrum Disorders (ASD), as the underlying
mechanisms remain poorly understood. Recent studies have implicated the cerebellum in the pathogenesis of
ASDs2-5, while we have recently shown that cerebellar dysfunction is sufficient to generate ASD-relevant
behaviors6. Although abnormalities in specific cerebellar regions have been identified in clinical ASD studies,
the exact functions of these cerebellar domains and the neural circuit basis by which these domains regulate
ASD behaviors remains poorly understood.
In this proposal, we present data demonstrating a critical role for the clinically-implicated, cerebellar domain
right CrusI7 in the regulation of ASD-related behaviors. Moreover, we also show that modulation of this region
during adulthood is able to partially rescue ASD-related behaviors in an ASD mouse model. However,
important questions remain including whether critical periods contribute to this incomplete cerebellar-mediated
rescue. We hypothesize that developmental critical time windows will impact rescue of ASD-related behaviors.
To evaluate these hypotheses, we propose experiments in Aim 1 to establish the critical periods regulating
In addition, considering a growing literature demonstrating the presence of cerebellar-cerebro cortical circuits5,
another unanswered question is whether the cerebellum regulates ASD behaviors through modulation of
cortical domains? We have generated preliminary data demonstrating connectivity between the cerebellum
and the clinically-implicated medial prefrontal cortex (mPFC) as well as data supporting a role for the mPFC in
cerebellar-regulated ASD behaviors. Based on these data, we hypothesize that cerebellar regulation of the
mPFC will contribute to ASD behaviors and that thalamo-cortical circuits will provide an anatomic substrate for
these cerebellar-regulated ASD behaviors. To address these hypotheses, we propose experiments in Aims 2
and 3 to further establish the functional relevance of cerebellar-mPFC connectivity, to determine the anatomic
basis for this connectivity in the regulation of ASD-related behaviors, and to uncover whether modulation of
these circuits can improve ASD-related behaviors.
Thus, in this proposal, we will establish the developmental time windows during which rescue of cerebellar-
mediated ASD behaviors can be achieved. We will additionally seek to identify and establish the role for
cerebellar-mPFC circuits in ASD-related behaviors and define the therapeutic benefits of circuit modulation on
these behaviors. Thus, these studies will not only further our understanding of basic mechanisms of ASD but
will also evaluate the pre-clinical potential for therapeutics using circuit-based neuromodulation for the
treatment of ASD.