Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors Efrain C. Azmitia a, b, * , Jorawer S. Singh a, b , Patricia M. Whitaker-Azmitia c a Dept. of Biology, New York University,100 Washington Sq East, New York, NY 11791, United States b Dept. of Psychiatry, New York University,100 Washington Sq East, New York, NY 11791, United States c Dept. of Psychology, Stony Brook University, Stony Brook, NY 11794, United States article info Article history: Received 16 August 2010 Received in revised form 4 November 2010 Accepted 1 February 2011 Keywords: Cerebral cortex Stress Morphometrics Medial forebrain bundle Ansa lenticularis abstract Imaging studies of serotonin transporter binding or tryptophan retention in autistic patients suggest that the brain serotonin system is decreased. However, treatment with drugs which increase serotonin (5-HT) levels, specific serotonin reuptake inhibitors (SSRIs), commonly produce a worsening of the symptoms. In this study we examined 5-HT axons that were immunoreactive to a serotonin transporter (5-HTT) antibody in a number of postmortem brains from autistic patients and controls with no known diagnosis who ranged in age from 2 to 29 years. Fine, highly branched, and thick straight fibers were found in forebrain pathways (e.g. medial forebrain bundle, stria terminalis and ansa lenticularis). Many immu- noreactive varicose fine fibers were seen in target areas (e.g. globus pallidus, amygdala and temporal cortex). Morphometric analysis of the stained axons at all ages studied indicated that the number of serotonin axons was increased in both pathways and terminal regions in cortex from autism donors. Our findings provide morphological evidence to warrant caution when using serotonin enhancing drugs (e.g. SSRIs and receptor agonist) to treat autistic children. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Autism spectrum disorder (ASD) is a group of neuro- developmental disorders defined by social and communication deficits as well as restricted behaviors. The Centers for Disease Control states that the average prevalence of ASDs identified among children aged 8 years increased 57% in 10 sites in USA from 2002 to 2006. Incidence of ASD worldwide is not uniform, with regional variations from 1.1/1000 in China (Zhang and Ji, 2005) to 9.1/1000 in the most recent findings in the US. This is an incidence greater than both childhood cancers and diabetes combined, yet little is known about autism’s cause, prevention or treatment. Originally described as one of the most heritable mental illnesses (Bailey et al., 1995), recent re-evaluation of this description has shown methodological biases, misinterpretations, and erroneous assumptions in much of the original data (Chamak, 2010). The more likely explanation is that autism occurs in response to an environmental factor. Elevated prenatal cortisol due to stress is associated with several negative conditions including aborted fetuses, excessive fetal activity, delayed fetal growth and development, premature delivery, low birth-weight, attention and temperament problems in infancy, externalizing problems in childhood, psychopathology, and chronic illness in adulthood (Field and Diego, 2008) and many studies indicate that increased stress (either psychological or physical) during pregnancy presents a significant risk factor for the occurrence of autism. These stressful events; such as infection, bereavement, depression, socioeconomic stress, vaginal bleeding, and threatened miscarriage may seem diverse, but all present one common endophenotype e activation of the homeostatic mecha- nisms of the hypothalamicepituitaryeadrenal (HPA) axis, elevating blood cortisol levels. In turn, the increase in cortisol may act as an epigenetic factor e changing the developmental trajectory of neuronal maturation necessary for normal function. A variety of obstetrical complications have been associated with an increased risk of autism, including bleeding during pregnancy (Brimacombe et al., 2007; Juul-Dam et al., 2001), low Apgar scores (Larsson et al., 2005; Glasson et al., 2004), long labors or precipitous labor (Glasson et al., 2004), threatened abortion (Glasson et al., 2004), induced labor (Brimacombe et al., 2007; Glasson et al., 2004), and breech presentation. Psychologically, pregnant women who report sadness (Zhang et al., 2010), anxiety or adverse life events (Beversdorf et al., 2005), physical stress (including exposure to storms) (Kinney et al., 2008), were all at greater risk of giving * Corresponding author. Tel.: þ1 212 998 8235. E-mail address: eca1@nyu.edu (E.C. Azmitia). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.02.002 Neuropharmacology 60 (2011) 1347e1354