Cerebellar Neuropathology Influences Cerebellar-Prefrontal Cortex Pathways: A Comprehensive Approach as Relevant to Autism Spectrum Disorders

The cognitive and social dexterity of humans is attributed to the neocortex, an area of the brain well accepted to elevate us beyond the mental processing of all other species. The cognitive ability of the cerebellum however, remains one of the most misunderstood. Autism spectrum disorders (ASDs), with a prevalence of 1 in 68 children, lack clear empirical explanations for abnormal neuropathology and potential neuronal disconnections influenced by the cerebellum. The current evaluation takes a comprehensive look at how the cerebellum, pre-frontal cortex, and basal ganglia are interconnected and influenced by each other as relevant to ASDs. With a better understanding of deep cerebellar influence from the dentate nucleus (DN) evoking dopamine release in the striatum, nucleus accumbens, and the medial prefrontal cortex (mPFC) allows for better understanding of modulation of these nuclei. The studied nuclei have a great impact on cognitions, reward systems, social and executive functions within both a typical developing brain as well as the ASDs brain. The presence of null findings in the Fmr1 mouse when exploring aspects of the striatum and accumbens are contrary to previous evidence showing DN modulation via the ventral tegmental area (VTA), however it notes the importance of exploring the same research paradigm within the Lurcher mouse strain to explore differences in Purkinje cell dysfunction as compared to absence. Interestingly two forms of compensation where observed in the Lurcher mutant strain in mPFC dopamine release via the VTA and the mediodorsal thalamus (ThN md) with a shift in strength towards the mutant strain within the VTA, and contrarily a shift in strength towards the wildtype strain in the ThN md, with null findings in the ventrolateral thalamus (ThN vl). These results lend further support to the Autism disconnection hypothesis that there is in some form an attenuation between the DN and the mPFC via a variety of nuclei. The current findings can inform future directions that include potential treatment interventions by means of a variety of therapeutic techniques including deep brain stimulation, pharmaceutical approaches, viral vectors and others, to alleviate some of the debilitating symptoms of ASDs