UC San Diego

Autism is a neurodevelopmental disorder of social cognition that is marked by frontally pronounced early brain overgrowth. Functional magnetic resonance imaging studies have shown that the regions of the brain that display the greatest overgrowth early in life, such as dorsolateral prefrontal cortex, also demonstrate significant deficits in older children and adults with the disorder. However, there is relatively little information about the cellular abnormalities that underlie these observed macrostructural and functional alterations. A single study has directly observed altered glial morphology in the postmortem autistic frontal cortex, while a handful of studies have observed neuron loss in older subjects with autism. Therefore, we conducted a series of experiments aimed at elucidating both population and organizational abnormalities in the microglial and neuronal populations in the autistic dorsolateral prefrontal cortex. In chapter II of this thesis, we use optical disector and isotropic nucleator to describe Iba-1 positive microglial density and volume in an unprecedentedly large sample of postmortem autism tissue. Our findings indicate that increased density and somal volume are present in a sizeable fraction of subjects with autism from an early age, including during the period of early brain overgrowth, and that these alterations are not attributable to seizure. In chapter III, we turn to an examination of average horizontal neuron distance in the same set of subjects. We describe an increase in horizontal neuronal spacing early in life that likely reflects an early overproduction of neuropil, while confirming previous findings of reduced horizontal distance in adults, suggesting a gradual degenerative decline. In chapter IV, we turn to spatial pattern analysis to examine whether there are alterations in neuronal and microglial organization. We discover emergent alterations in local neuron-neuron and microglia-microglia organization across the autistic lifespan, along with group differences in local microglia-neuron clustering that do not show a developmental trend. These experiments describe several novel microstructural features of the developing autistic brain, and suggest that microglial activation and neuropil overproduction are present during early brain overgrowth and are followed by gradual neuropil degeneration and loss of cellular organization in adolescents and adults that may be related at least in part to ongoing microglial activation. Further investigation of cellular and microstructural abnormalities in the autistic brain may hold the key to understanding the complex set of alterations that underlie this disorder, and point the way towards diagnostic strategies and therapeutic instruments