Neurobiological investigations of autism symptomatology and cerebellar pathology

Abstract

The cerebellum is the most commonly reported brain region to demonstrate pathology in autism. Multiple reports have indicated a lower density of Purkinje cells (PCs) in the posterolateral cerebellar hemispheres. We performed a stereological technique to precisely quantify PCs in postmortem autism cases compared to age- and sex-matched controls. We found that although PC density was lower in all cerebellar regions studied, the most significant difference was in lobule VIIa of the posterior lobe. The PCs in this region project to deep cerebellar nuclei that reciprocally connect to all aspects of the established broader sensorimotor gating network. Sensorimotor gating abnormalities are commonly observed in individuals diagnosed with autism, and may contribute to problems with sensory processing and behavioral inhibition in these individuals. We studied a rat model of sensorimotor gating impairment, in which the histamine H1 receptor antagonist, pyrilamine, improved sensorimotor gating. Using autoradiography, we found that pyrilamine treatment altered H1 receptor and α7 nicotinic receptor binding in the anterior cingulate and insular cortex, respectively, an effect which correlated with improved sensorimotor gating. Histamine functions as both a neurotransmitter as well as a regulator of glial activity throughout the brain. Using western blots, we quantified H1 receptor levels in lobule VIIa from postmortem autism cases but found no difference compared to controls. We further quantified additional proteins to investigate theories of neuroimmune and neuroendocrine dysregulation in the cerebellum in autism. These included IBA-1, GFAP, IL-6, androgen receptor, estrogen receptor β, and aromatase. We found no evidence to support these theories: all protein levels tested were found to be similar in the autism and control groups. We suggest further studies to better understand cerebellar pathogenesis and regulation of sensorimotor gating in autism. The implications of sensorimotor gating impairment in autism are discussed in relation to the established symptomatology of this neurodevelopmental behavioral disorder.