Neuroanatomy of autism: what is the role of the cerebellum?

Abstract

Autism (or autism spectrum disorder) was initially defined as a psychiatric disorder, with the likely cause maternal behavior (the very destructive "refrigerator mother" theory). It took several decades for research into brain mechanisms to become established. Both neuropathological and imaging studies found differences in the cerebellum in autism spectrum disorder, the most widely documented being a decreased density of Purkinje cells in the cerebellar cortex. The popular interpretation of these results is that cerebellar neuropathology is a critical cause of autism spectrum disorder. We challenge that view by arguing that if fewer Purkinje cells are critical for autism spectrum disorder, then any condition that causes the loss of Purkinje cells should also cause autism spectrum disorder. We will review data on damage to the cerebellum from cerebellar lesions, tumors, and several syndromes (Joubert syndrome, Fragile X, and tuberous sclerosis). Collectively, these studies raise the question of whether the cerebellum really has a role in autism spectrum disorder. Autism spectrum disorder is now recognized as a genetically caused developmental disorder. A better understanding of the genes that underlie the differences in brain development that result in autism spectrum disorder is likely to show that these genes affect the development of the cerebellum in parallel with the development of the structures that do underlie autism spectrum disorder.

Keywords: Fragile X syndrome; Joubert syndrome; Purkinje cells; tuberous sclerosis.

Fig. 1

The cerebellum in humans, chimpanzee, monkey, cat, and rat. A, B) Two different views of a human cerebellum; cerebellum of case 178 from the Witelson normal brain collection (Witelson and McCulloch 1991). The cerebellum has been stored in 10% formalin; it was photographed with an iPhone 14. C) Cresyl violet (a Nissl stain) stained section of human cerebellar cortex, case 155 from the Witelson Normal Brain Collection, showing the gr cell layer with many stained neurons, the outer ml layer and the Purkinje cell layer: The small black arrows indicate 2 stained Purkinje cells. This image and the images shown in d to i were captured with a SPOT Insight Color Mosaic camera (1600 × 1200 pixels) mounted on a Leitz Dialux 20 microscope. Brightness, contrast, and color of the images were adjusted and the figure assembled with Adobe Photoshop software (San Jose, CA). D) The cerebellar cortex in a section immunostained for a calcium-binding protein calbindin, expressed in Purkinje cells (Whitney et al. 2008b). The Purkinje cells (example at arrow) and their dendritic trees are immunostained. Case 164 from the Witelson Normal Brain Collection. E, F) Cerebellar cortex in the chimpanzee. We examined and photographed sections that had been prepared for an earlier project (Baizer et al. 2013). E) Cresyl violet-stained section showing cerebellar cortex, cerebellar wm, and one of the deep cerebellar nuclei (arrowhead). F) Section of chimpanzee cerebellum immunostained for calbindin, again clearly showing the layer of Purkinje cells (example at arrow). G) Cerebellar cortex and one of the deep cerebellar nuclei (arrowhead) in a macaque monkey. We photographed and archival slide of a Cresyl violet-stained section prepared by the Glickstein laboratory at Brown University. H) Cresyl violet-stained celloidin section from a cat brain (section also prepared by the Glickstein laboratory). In this section, the Purkinje cells (example at arrow) are more darkly stained than the gr cells. I) Section of the rat cerebellum stained with Cresyl violet to show neurons and Luxol fast blue to stain fibers (slide from the Glickstein laboratory). Scale bars: A, B = 1 cm; C, H, I = 250 μm; E, G = 500 μm; D, F = 100 μm.