Serotonin Axonal Pathways and Cortical Terminals In Autism; Evidence for Increased Fibers In Early Childhood and Dystrophic Fibers In Adolescence

Background: Serotonin plasma levels are increased in many autistic patients and death in children is often attributed to respiratory distress, cardiac failure, seizures, and hyperthermia which are components of the lethal Serotonin Syndrome attributed to high levels of brain serotonin.  In contrast, the associated symptoms shown by autism patients include aggression, hyper-sensensitivity, stereotypy, and self-induced aggression suggest a decrease serotonin system.  Imaging studies in autistic patients support this notion.  However, treatment with drugs which increase serotonin levels (e.g. SSRIs) produces a worsening of the symptoms.  

Objectives:  In this study we examined serotonin axons immunoreactive to 5-HT transporter (5-HTT) antibody in a number of postmortem brains from autistic and no known diagnosis (NKD, control) patients aged 2 to 34 years of age. 

Methods:  The postmortem brains were obtained from the Brain Bank for Disabilities and Aging in Staten Island, the Autism Tissue Program in Princeton New Jersey, and the NICHD Brain, and Tissue Bank for Developmental Disorders at University of Maryland, Baltimore. The brains were post-fixed in polyethylene glycol (PEG) so large sections could be cut that included temporal lobe cortices, hippocampus, and amygdala as well as underlying subcortical structures that included septum, hypothalamus, and striatum. 

Results: Fine and thick straight 5-HTT positive fibers were found in forebrain pathways (e.g. medial forebrain bundle, stria terminalis and ansa lenticularis) from both autistic and NKD donors.  Many highly branched 5-HTT immunoreactive varicose fine fibers were seen in target areas (e.g. globus pallidus, amygdala and temporal cortex).  The number of serotonin axons was significantly increased in both pathways and terminal regions in cortex using morphometric analysis of the stained axons at all ages studied. Dystrophic serotonin axons were apparent in the brains of adolescent children with autism.  Morphometric analysis showed a quadratic relationship between abnormal axons and age, with highest numbers appearing in adolescence.  The highest level of dystrophic axons was seen in a young teenager who died with a diagnosis of the Serotonin Syndrome. We conclude that serotonin axons are increased in the brains of autistic patients beginning at the youngest age examined (2.8 years) and stay elevated throughout adolescence when the serotonin fibers begin to degenerate. Degenerating serotonin fibers have been previously observed in older patients with neurodegenerative diseases (Azmitia and Nixon, 2008). 

 Conclusions:  The increased serotonin innervation is consistent with death associated with the serotonin syndrome.  However, it is hard to understand why SSRIs should make “serotonin-deficient” symptoms worse that are normally effectively treated with SSRI.   We propose high serotonin brain levels would result in a corresponding decrease in serotonin receptors, and result in “serotonin-deficient” symptoms.  This situation would be exasperated by increasing serotonin, which would further drive the receptors down.  An alternative treatment we propose is the use of atypical antipsychotics which have substantial 5-HT2A receptor antagonistic properties. We will discuss strategies for increasing serotonin receptors by use of an antagonist in brain (Abbas et al, 2007).