Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior

Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2012; 109(14):5469-74. DOI: 10.1073/pnas.1112345109
Source: PubMed

ABSTRACT Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.

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    ABSTRACT: Dysregulation of serotonin (5-HT) signaling underscores long-standing theories of circuit perturbations that lead to risks for mental disorders. 5-HT acts both as a morphogenetic factor during neural circuit formation and a neuromodulator of circuit plasticity in the mature CNS (Gaspar et al., 2003, Kandel, 2001 and Lesch and Waider, 2012). The 5-HT transporter (SERT) controls 5-HT signaling by limiting 5-HT availability to 5-HT receptors (Blakely and Edwards, 2012). Selective 5-HT reuptake inhibitors (SSRIs), which block SERT thus increasing 5-HT signaling, are the first-line treatments for psychiatric traits in adults. However, polymorphisms that reduce SERT gene Slc6a4 expression/functionality increase the risks for autism and depression and confer abnormal cortical anatomical architecture (Murphy and Lesch, 2008, Pezawas et al., 2005 and Veenstra-VanderWeele et al., 2012). In rodents, excessive 5-HT triggered by knocking out SERT or the 5-HT degradation enzyme monoamine oxidase A (MAOA) disrupts topographic patterning of the somatosensory barrel and visual cortex and causes anxiety-like behavior (Cases et al., 1996, Murphy and Lesch, 2008, Persico et al., 2001 and Upton et al., 2002). Furthermore, administration of SSRIs during the first 2 postnatal weeks was sufficient to confer altered CNS dendritic morphology and increased anxiety-like behavior (Rebello et al., 2014). These observations suggest that SERT exerts distinct biological roles in developing and adult CNS. The mechanism underlying SERT gene function in the developing CNS remains unclear.
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