Evaluation of Cerebellar-Cortical Circuitry Using Rodent Models: Relevance to Autism Spectrum Disorders

While the etiology of autism is unknown, current research indicates that abnormalities of the cerebellum, now believed to be involved in cognitive function, and the prefrontal cortex (PFC) are associated with autism. The current paper proposes that impaired cerebello-cortical circuitry could, at least in part, underlie autistic symptoms. The evidence linking the cerebellum to autism and rodent models useful for elucidating etiological factors in autism as well as their potential impact on cerebello-cortical circuitry are reviewed. Recent research has demonstrated in wildtype mice that stimulation of the dentate nucleus of the cerebellum (DN) evokes dopamine release in the medial prefrontal cortex (mPFC). Therefore the current paper also investigated the neuronal circuitry by which the cerebellum modulates mPFC dopamine release in mice. Fixed potential amperometry was used to determine the contribution of two candidate pathways by which the cerebellum may modulate mPFC dopamine release. In urethane anesthetized wildtype mice, dopamine release evoked by DN stimulation was recorded in mPFC following local anesthetic lidocaine or ionotropic glutamate receptor antagonist kynurenate infusions into the mediodorsal or ventrolateral thalamic nucleus (ThN md; ThN vl), or the ventral tegmental area (VTA). Also, to identify any compensatory changes within the neural circuitry following a developmental cerebellar pathology, mPFC dopamine release evoked by DN stimulation was recorded using the same methodology in two mutant models: the FMR1 mutant mouse which has elongated Purkinje cell spines and decreased volume of deep cerebellar nuclei, and Lurcher mutant mouse, which loses almost all Purkinje cells between the second and fourth weeks of life. While the cerebello-thalamo-cortical and cerebello-ventral tegmento-cortical pathways contributed equally to cerebellar modulation of PFC dopamine release in wildtype mice, modulatory control shifted to the thalamus in both mutant mouse strains. Also, reductions in dopamine release following lidocaine or kynurenate infusions were not significantly different indicating that neuronal cells in the VTA and ThN were activated primarily if not entirely by glutamatergic inputs. The current findings suggest that a loss or impairment of cerebellar output has downstream effects on cerebellar-cortical circuitry that could account for certain symptoms of autism