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: 9.67). 03/2012; 109(14):5469-74. DOI: 10.1073/pnas.1112345109
Source: PubMed


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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    • "Recent findings from studying the relationship of hyperserotonemia and ASD suggest that 5HT 2A receptor antagonists represent one promising treatment approach [Veenstra-VanderWeele et al., 2012]. Elevated whole-blood 5HT or hyperserotonemia is a consistent finding in approximately 30% of ASD individuals [Cook & Leventhal, 1996; Mulder et al., 2004]. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with restricted interests and repetitive behaviors (RRBs). RRBs can severely limit daily living and be particularly stressful to family members. To date, there are limited options for treating this feature in ASD. Risperidone, an atypical antipsychotic, is approved to treat irritability in ASD, but less is known about whether it is effective in treating “higher order” RRBs, for example cognitive inflexibility. Risperidone also has multiple receptor targets in which only a subset may be procognitive and others induce cognitive impairment. 5HT2A receptor blockade represents one promising and more targeted approach, as various preclinical studies have shown that 5HT2A receptor antagonists improve cognition. The present study investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist, improved probabilistic reversal learning performance in the BTBR T + tf/J (BTBR) mouse model of autism. The effects of these treatments were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, similar to one in which ASD individuals exhibit impairments, both risperidone (0.125 mg) and M100907 (0.01 and 0.1 mg) improved reversal learning in BTBR mice. Risperidone (0.125 mg) impaired reversal learning in B6 mice. Improvement in probabilistic reversal learning performance resulted from treatments enhancing the maintenance of the newly correct choice pattern. Because risperidone can lead to unwanted side effects, treatment with a specific 5HT2A receptor antagonist may improve cognitive flexibility in individuals with ASD while also minimizing unwanted side effects. Autism Res 2014, ●●: ●●–●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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    • "A SLC6A4 variant coding for an overactive form of 5-HTT has been identified in families of autistic patients (Sutcliffe et al., 2005). Mutant mice expressing this high functioning 5-HTT variant show hyperserotonemia, hypersensitivity of 5-HT receptors (as a result of reduced serotonergic transmission) and autistic behavior (Veenstra-VanderWeele et al., 2012). "
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    • "Additionally, the DRN 5-HT system has been implicated in the pathophysiology and therapeutics of mental disorders such as depression, anxiety, autism, etc. . .(Stockmeier, 1997; Arango et al., 2001; Bach- Mizrachi et al., 2006, 2008; Bruchas et al., 2011; Matthews and Harrison, 2012; Kerman et al., 2012; Veenstra-VanderWeele et al., 2012). Dysfunction of 5-HT neurotransmission associated with these disorders may reflect alterations in axonal networks and synaptic circuits within the DRN. "
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    ABSTRACT: The dorsal raphe nucleus (DRN), representing the main source of brain's serotonin, is implicated in the pathophysiology and therapeutics of several mental disorders that can be debilitating and life-long including depression, anxiety and autism. The activity of DRN neurons is precisely regulated, both phasically and tonically, by excitatory glutamate and inhibitory GABAergic axons arising from extra-raphe areas as well as from local sources within the nucleus. Changes in serotonin neurotransmission associated with pathophysiology may be encoded by alterations within this network of regulatory afferents. However, the complex organization of the DRN circuitry remains still poorly understood. Using a recently developed high-resolution immunofluorescence technique called array tomography (AT) we quantitatively analyzed the relative contribution of different populations of glutamate axons originating from different brain regions to the excitatory drive of the DRN. Additionally, we examined the presence of GABA axons within the DRN and their possible association with glutamate axons. In this review, we summarize our findings on the architecture of the rodent DRN synaptic neuropil using high-resolution neuroanatomy, and discuss possible functional implications for the nucleus. Understanding of the synaptic architecture of neural circuits at high resolution will pave the way to understand how neural structure and function may be perturbed in pathological states.
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