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, social networks) rather than considering global chemical neural systems. Serotonergic neurons have a global innervation pattern. 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 post-mortem brain tissue from autism donors aged 2.8 to 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 eight 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 a diet therapy may be effective to blunt serotonin’s trophic actions during early brain development in children.

Evidence for dysregulation of axonal growth and guidance in the etiology of ASD

“…Axons in the superficial white matter below the orbitofrontal exhibited significantly thinner myelin sheaths when controlled for axon diameter despite similar numbers of oligodendrocytes (Zikopoulos and Barbas, 2010). Azmitia et al (2010, 2011) also found a significant excess of morphologically abnormal serotonin axons in principle ascending fiber bundles of the medialand lateral forebrain bundles as well as target areas in the temporal cortex, amygdala, and globus pallidus.…”

Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats

“…An increased number of dystrophic thick SERT-ir fibers has been noted in the amygdala, the hippocampus, and the cortex of autistic patients (Azmitia et al, 2011). Interestingly, rodents exposed neonatally to CTM showed an increased number of thick and rod-like SERT-ir fibers and/or fine and beaded SERT-ir fibers in the cortex and hippocampus (Maciag et al, 2006; Weaver et al, 2010).…”

Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum

“…The areas for analysis were photographed from coded slides to include layers II– V of the temporal and fusiform cortices, midbrain tegmentum, pontine fibers and cerebellar cortex. All pictures were stored by code for analysis using NIH ImageJ as previously described (see Akbari et al 1994; Azmitia et al 2011a, b). Stereological measures were made directly from the brain slides as previously described (Boldrini et al 2012).…”