Defects of Cholinergic Neurons Development In Autism

Background:  

Nucleus basalis of Meynert (NBM), consists of four major nuclei (Ch1–4) that send cholinergic, GABAergic and glutamatergic axons to the cortical mantle (Henny and Jones, Eur. J. Neurosc. 2008, 27, 654-670). Cholinergic drive to the forebrain plays a modulatory role in anxiety, arousal and attention, and is essential for many learning and memory tasks (Murray and Fibiger, Neuroscience 1985, 14, 1025-1032; Kilgard, Neuron 2003, 38, 678-680). Autism is associated with signs of developmental alterations of the cortex, including abnormal structure of minicolumns and curtailed neuron development (Casanova et al., Neurology, 2002, 58, 428-432). However, one may hypothesize that cortical functional alterations are combined effects of cortical developmental alterations and abnormal cholinergic modulation due to developmental defects of the NBM.

Objectives: The aim of this study is to test the hypothesis that development of cholinergic neurons of the NBM is modified in autistic subjects. 

Methods:  Unbiased morphometric methods were applied to characterize four nuclei of the NBM in 12 autistic (4-64 years old) and 12 control (4 to 64 years old) subjects. The fractionator method was used to determine the number of neurons, the Cavalieri method to estimate the volume of the NBM, and Nucleator method to determine the volume of neurons and neuronal nuclei (Microbrightfield, VT).

Results:  General linear models (GLM), with age group (4-8 years vs. over 8-years of age) as a between-subject effect, and autistic status and the interaction of autistic status and age groups as within-subject effect, were used to examine the combined effects of age and autistic status on neuronal and nuclear volume. Autistic subjects had reduced neuronal volume (F = 13.161, p = .005); this was also a non-significant trend for younger subjects (F = 3.942, p = .075). A significant interaction of younger age and autistic status was observed (F = 5.395, p = .043), indicating that the association between autism and a reduced volume of neurons was most pronounced in the youngest subjects. Autistic subjects also had reduced nuclear volume (F = 15.434, p = .003). A significant interaction of younger age and autistic status was observed for nuclear volume as well (F = 8.169, p = .017), indicating that the association between autism and reduced nuclear volume was also most pronounced in the youngest subjects.

Conclusions:  Reduced volume of neurons in the NBM of autistic subjects may reflect altered cholinergic innervation of the cortical mantle contributing to anxiety, arousal, deficit of attention, and learning difficulties.