Dystrophic serotonin axons in postmortem brains from young autism patients

Abstract

Autism causes neuropathological changes in varied anatomical loci. A coherent neural mechanism to explain the spectrum of autistic symptomatology has not been proposed because most anatomical researchers focus on point-to-point functional neural systems (e.g., auditory and social networks) rather than considering global chemical neural systems. Serotonergic neurons have a global innervation pattern. Disorders Research Program, AS073234, Program Project (JW). Their cell bodies are found in the midbrain but they project their axons throughout the neural axis beginning in the fetal brain. This global system is implicated in autism by animal models and by biochemical, imaging, pharmacological, and genetics studies. However, no anatomical studies of the 5-HT innervation of autistic donors have been reported. Our review presents immunocytochemical evidence of an increase in 5-HT axons in postmortem brain tissue from autism donors aged 2.8-29 years relative to controls. This increase is observed in the principle ascending fiber bundles of the medial and lateral forebrain bundles, and in the innervation density of the amygdala and the piriform, superior temporal, and parahippocampal cortices. In autistic donors 8 years of age and up, several types of dystrophic 5-HT axons were seen in the termination fields. One class of these dystrophic axons, the thick heavily stained axons, was not seen in the brains of patients with neurodegenerative diseases. These findings provide morphological evidence for the involvement of serotonin neurons in the early etiology of autism, and suggest new therapies may be effective to blunt serotonin's trophic actions during early brain development in children.

Figure 1

This figure shows axons reactive to the 5-HTT antibody in the Medial Forebrain Bundle of young autism donors and typical controls. It can be seen that there are many more intensely labeled axons in the autism donor than in the control at this early age. Scale bar is 50 micrometers.

Figure 2

This figure shows axons reacting to the 5-HTT antibody in the fusiform cortex of two autism patients and one control with No Known Diagnosis. In both the two year nine month and twenty nine year old autism patients, there are many more 5-HTT axons in Layers I–IV. Notice that in the 29 year old, there are a number of dystrophic immunoreactive profiles seen in Layers II–IV (arrows). The bar is 100 micrometers.

Figure 3

This figure shows 5-HTT immunoreactive axons in the various terminal areas including the amygdala, Superior Temporal Cortex (STC), and in the Fusiform Cortex. Note the relative absence of dystrophic fibers in the amygdala of control donors at both 2.1 and 25 years and in the autism donor at 2.8 years. Dystrophic profiles immunoreactive to 5-HTT antibodies are seen in amygdala, STC, and Fusiform Cortex in autism donors 8–29 years of age.

Figure 4

This figure shows a 5-HTT immunoreactive dystrophic axon in Layer II of the Superior Temporal Cortex at three different magnifications. The location of the high magnification pictures are indicated in Panel A with the letters B and C. The thick, relatively straight axon has irregularly spaced round and elliptical shaped varicosities. Many fine, highly branched 5-HTT immunoreactive axons can be seen in Layers I, II, and III (Panel A). These axons have regularly spaced spherical varicosities. Bars are 100, 50, and 20 micrometers for Panels A through C respectively.