Gender-Specific Effect of 5-HT and 5-HIAA on Threshold Level of Behavioral Symptoms and Sex-Bias in Prevalence of Autism Spectrum Disorder

Abstract

Platelet hyperserotonemia in a subset of Autism Spectrum Disorder (ASD) probands, efficacy of selective serotonin reuptake inhibitors (SSRIs) in reducing behavioral deficits and gender-bias in normal serotonin (5-hydroxy tryptamine or 5-HT) synthesis suggest disruption in stringent regulation of serotonin metabolism in ASD. Therefore, we investigated the changes in 5-HT and 5-hydroxy indole acetic acid (5-HIAA) in ASD probands to assess its effect on the behavior of male and female probands. ASD cases (n = 215) were examined using childhood autism rating scale (CARS). Platelet 5-HT (104 cases and 26 controls) and platelet/plasma 5-HIAA (73 cases and 17 controls) were estimated using high performance liquid chromatography coupled with electrochemical detector (HPLC-ECD). In male probands, we observed increase in platelet 5-HT content in association with increase in the score for adaptive responses and increase in platelet 5-HIAA levels with concomitant decline in the score for intellectual response. Age did not influence the neurochemical parameters, but imitation, listening responses and nonverbal communication scores decreased with age. Conversely in female probands, plasma 5-HIAA level significantly attenuated with age, when platelet 5-HT content remained unchanged. Interestingly, platelet/plasma 5-HT and plasma 5-HIAA were higher in female controls. Female probands displayed severe autism-associated behaviors. Overall results indicate gender-bias in 5-HT and 5-HIAA regulation, which probably increases the threshold level of ASD phenotypes in the females, thereby affecting ASD prevalence in a sex-specific manner.

Birth related parameters are important contributors in autism spectrum disorders

“…Interestingly, on separating the males from the females it was found that the males have a lower mean CARS score (34.35) as compared to the females (36.76), indicating disease severity was more in the females than in the males, even though the frequency of occurance is much less in the females. This is similar to a previous observation found in another population of the same state 26 . They showed that, higher platelet/plasma 5-HT and plasma 5-HIAA in the females could probably increase the threshold level of ASD phenotypes in the females, thereby contributing to more severe phenotypes.…”

Sex Differences in Tryptophan Metabolism: A Systematic Review Focused on Neuropsychiatric Disorders

“…On the other hand, for disorders that affect more men than women, sexual dimorphisms on Tryp metabolism and its possible relationship with pathological onset and progression are not so clear. On one hand, for ASD and schizophrenia, sexual dimorphisms on Tryp metabolism reveal that men, compared with women, have increased production of 5-HT [ 126 , 127 ] and KYNA [ 122 ], respectively. Similarly, patients with those conditions also exhibit the same dysfunctions compared to healthy controls [ 9 , 10 , 15 ].…”

Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity

“…Markers of platelet activation, elevated platelets, and serotonin levels have also been reported in ASD patients. In fact, gender specific effects of serotonin signaling may impact threshold levels of ASD phenotypes [ 133 ]. Several reports suggest that serotonin, acting thru 5-HT2B receptor, likely controls the M1 (inflammatory) vs. M2 (anti-inflammatory) status of microglia, thereby impacting synaptic development/numbers, and altering synaptic plasticity/excitatory neurotransmission [ 128 , 134 , 135 , 136 ].…”