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Nod-like receptors are critical for gut-brain axis signalling in mice.
Pusceddu MM, Barboza M, Keogh CE, Schneider M, Stokes P, Sladek JA, Kim HJD, Torres-Fuentes C, Goldfild LR, Gillis SE, Brust-Mascher I, Rabasa G, Wong KA, Lebrilla C, Byndloss MX, Maisonneuve C, Bäumler AJ, Philpott DJ, Ferrero RL, Barrett KE, Reardon C, Gareau MG
(2019) J Physiol 597: 5777-5797
MeSH Terms: Animals, Anxiety, Brain, Cells, Cultured, Cognition, Female, Hypothalamo-Hypophyseal System, Intestinal Absorption, Intestinal Mucosa, Male, Mice, Mice, Inbred C57BL, Neurogenesis, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Serotonin, Stress, Psychological, Synaptic Transmission
Show Abstract · Added March 30, 2020
KEY POINTS - •Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. •Nod-like receptors regulate central and peripheral serotonergic biology. •Nod-like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour.
ABSTRACT - Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre Nod1 ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.
© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.
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18 MeSH Terms
Association between First Trimester Antidepressant Use and Risk of Spontaneous Abortion.
Wu P, Velez Edwards DR, Gorrindo P, Sundermann AC, Torstenson ES, Jones SH, Chan RL, Hartmann KE
(2019) Pharmacotherapy 39: 889-898
MeSH Terms: Abortion, Spontaneous, Adult, Antidepressive Agents, Female, Humans, Pregnancy, Pregnancy Trimester, First, Proportional Hazards Models, Prospective Studies, Serotonin Uptake Inhibitors, United States, Young Adult
Show Abstract · Added August 5, 2020
STUDY OBJECTIVE - The potential for maternal antidepressant use to influence the risk of spontaneous abortion, one of the most important adverse pregnancy outcomes, is not clear. We aimed to assess whether first trimester antidepressant exposure was associated with an increased risk of spontaneous abortion.
DESIGN - Community-based prospective cohort study (Right from the Start).
SETTING - Eight metropolitan areas in North Carolina, Tennessee, and Texas.
PARTICIPANTS - A total of 5451 women (18 years of age or older) who were planning to conceive or were pregnant (before 12 weeks of completed gestation) and were enrolled in the study between 2000 and 2012; of those women, 223 used antidepressants (selective serotonin reuptake inhibitors [SSRIs] only [170], SSRIs and non-SSRIs [9], and non-SSRIs only [44]) during their first trimester, and 5228 did not (never users). Measurements and Main Results First trimester antidepressant use was determined during a first trimester telephone interview. Spontaneous abortion was self-reported and verified by medical records. The association of first trimester antidepressant use and spontaneous abortion was assessed by using Cox proportional hazard regression. Among the 5451 women enrolled, 223 (4%) reported first trimester antidepressant use, and 659 (12%) experienced a spontaneous abortion. SSRIs were the most common class of antidepressants used (179 [80%]). Compared with women who never used antidepressants during the first trimester of pregnancy, women who reported antidepressant use were 34% (adjusted hazard ratio [aHR] 1.34, 95% confidence interval [CI] 0.97-1.85) more likely to experience a spontaneous abortion after adjusting for covariates. Women who reported ever using SSRIs were 45% (aHR 1.45, 95% CI 1.02-2.06) more likely to experience a spontaneous abortion compared with never users. When time of loss relative to the time of interview was taken into consideration, the association between first trimester SSRI use and spontaneous abortion was significant only among those with losses before the interview (aHR 1.49, 95% CI 1.04-2.13) but was not significant among those with losses after the interview (aHR 0.43, 95% CI 0.06-3.15).
CONCLUSION - The association between use of first trimester antidepressants, particularly SSRI use, and spontaneous abortion was significant only among women whose exposure status was assessed after loss. In this instance, reporting bias may create a spurious association. Future studies should take the timing of data collection relative to the timing of loss into consideration.
© 2019 Pharmacotherapy Publications, Inc.
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Sex-Dependent Modulation of Anxiety and Fear by 5-HT Receptors in the Bed Nucleus of the Stria Terminalis.
Marcinkiewcz CA, Bierlein-De La Rosa G, Dorrier CE, McKnight M, DiBerto JF, Pati D, Gianessi CA, Hon OJ, Tipton G, McElligott ZA, Delpire E, Kash TL
(2019) ACS Chem Neurosci 10: 3154-3166
MeSH Terms: Animals, Anxiety, Behavior, Animal, Fear, Feeding Behavior, Female, Gene Knockdown Techniques, Male, Mice, Mice, Transgenic, Motor Activity, Neurons, Receptor, Serotonin, 5-HT1A, Septal Nuclei, Sex Factors
Show Abstract · Added June 28, 2019
Serotonin (5-hydroxytryptamine; 5-HT) coordinates behavioral responses to stress through a variety of presynaptic and postsynaptic receptors distributed across functionally diverse neuronal networks in the central nervous system. Efferent 5-HT projections from the dorsal raphe nucleus (DRN) to the bed nucleus of the stria terminalis (BNST) are generally thought to enhance anxiety and aversive learning by activating 5-HT receptor (5-HTR) signaling in the BNST, although an opposing role for postsynaptic 5-HT receptors has recently been suggested. In the present study, we sought to delineate a role for postsynaptic 5-HT receptors in the BNST in aversive behaviors using a conditional knockdown of the 5-HT receptor. Both males and females were tested to dissect out sex-specific effects. We found that male mice have significantly reduced fear memory recall relative to female mice and inactivation of 5-HT receptor in the BNST increases contextual fear conditioning in male mice so that they resemble the females. This coincided with an increase in neuronal excitability in males, suggesting that 5-HT receptor deletion may enhance contextual fear recall by disinhibiting fear memory circuits in the BNST. Interestingly, 5-HT receptor knockdown did not significantly alter anxiety-like behavior in male or female mice, which is in agreement with previous findings that anxiety and fear are modulated by dissociable circuits in the BNST. Overall, these results suggest that BNST 5-HT receptors do not significantly alter behavior under basal conditions, but can act as a molecular brake that buffer against excessive activation of aversive circuits in more threatening contexts.
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15 MeSH Terms
Human Serotonin Transporter Coding Variation Establishes Conformational Bias with Functional Consequences.
Quinlan MA, Krout D, Katamish RM, Robson MJ, Nettesheim C, Gresch PJ, Mash DC, Henry LK, Blakely RD
(2019) ACS Chem Neurosci 10: 3249-3260
MeSH Terms: Animals, CHO Cells, Cricetulus, Fenfluramine, Hippocampus, Humans, Mice, Neurons, Protein Conformation, Serotonin, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors
Show Abstract · Added February 22, 2019
The antidepressant-sensitive serotonin (5-HT) transporter (SERT) dictates rapid, high-affinity clearance of the neurotransmitter in both the brain and periphery. In a study of families with multiple individuals diagnosed with autism spectrum disorder (ASD), we previously identified several, rare, missense coding variants that impart elevated 5-HT transport activity, relative to wild-type SERT, upon heterologous expression as well as in ASD subject lymphoblasts. The most common of these variants, SERT Ala56, located in the transporter's cytosolic N-terminus, has been found to confer in transgenic mice hyperserotonemia, an ASD-associated biochemical trait, an elevated brain 5-HT clearance rate, and ASD-aligned behavioral changes. Hyperfunction of SERT Ala56 has been ascribed to a change in 5-HT , though the physical basis of this change has yet to be elucidated. Through assessments of fluorescence resonance energy transfer (FRET) between cytosolic N- and C-termini, sensitivity to methanethiosulfonates, and capacity for N-terminal tryptic digestion, we obtain evidence for mutation-induced conformational changes that support an open-outward 5-HT binding conformation and . Aspects of these findings were also evident with another naturally occurring C-terminal SERT coding variant identified in our ASD study, Asn605. We conclude that biased conformations of surface resident transporters that can impact transporter function and regulation are an unappreciated consequence of heritable and disease-associated SERT coding variation.
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12 MeSH Terms
Serotonin transporter inhibition and 5-HT receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice.
Stewart A, Davis GL, Gresch PJ, Katamish RM, Peart R, Rabil MJ, Gowrishankar R, Carroll FI, Hahn MK, Blakely RD
(2019) Neuropsychopharmacology 44: 994-1006
MeSH Terms: Animals, Behavior, Animal, Cocaine, Conditioning, Classical, Disease Models, Animal, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Fluoxetine, Locomotion, Methylphenidate, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Neostriatum, Receptor, Serotonin, 5-HT2C, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors
Show Abstract · Added January 8, 2019
Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.
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19 MeSH Terms
Bone Marrow-Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Receptor Dependent Mechanism.
Bloodworth NC, Clark CR, West JD, Snider JC, Gaskill C, Shay S, Scott C, Bastarache J, Gladson S, Moore C, D'Amico R, Brittain EL, Tanjore H, Blackwell TS, Majka SM, Merryman WD
(2018) Circ Res 123: e51-e64
MeSH Terms: Angiogenesis Inhibitors, Animals, Arterioles, Cell Lineage, Cells, Cultured, Hypertension, Pulmonary, Indoles, Lung, Mice, Mice, Inbred C57BL, Myeloid Progenitor Cells, Pyrroles, Receptor, Serotonin, 5-HT2B, Vascular Stiffness
Show Abstract · Added April 2, 2019
RATIONALE - Pulmonary arterial hypertension is a deadly disease of the pulmonary vasculature for which no disease-modifying therapies exist. Small-vessel stiffening and remodeling are fundamental pathological features of pulmonary arterial hypertension that occur early and drive further endovascular cell dysfunction. Bone marrow (BM)-derived proangiogenic cells (PACs), a specialized heterogeneous subpopulation of myeloid lineage cells, are thought to play an important role in pathogenesis.
OBJECTIVE - To determine whether BM-derived PACs directly contributed to experimental pulmonary hypertension (PH) by promoting small-vessel stiffening through 5-HT (serotonin 2B receptor)-mediated signaling.
METHODS AND RESULTS - We performed BM transplants using transgenic donor animals expressing diphtheria toxin secondary to activation of an endothelial-specific tamoxifen-inducible Cre and induced experimental PH using hypoxia with SU5416 to enhance endovascular injury and ablated BM-derived PACs, after which we measured right ventricular systolic pressures in a closed-chest procedure. BM-derived PAC lineage tracing was accomplished by transplanting BM from transgenic donor animals with fluorescently labeled hematopoietic cells and treating mice with a 5-HT antagonist. BM-derived PAC ablation both prevented and reversed experimental PH with SU5416-enhanced endovascular injury, reducing the number of muscularized pulmonary arterioles and normalizing arteriole stiffness as measured by atomic force microscopy. Similarly, treatment with a pharmacological antagonist of 5-HT also prevented experimental PH, reducing the number and stiffness of muscularized pulmonary arterioles. PACs accelerated pulmonary microvascular endothelial cell injury response in vitro, and the presence of BM-derived PACs significantly correlated with stiffer pulmonary arterioles in pulmonary arterial hypertension patients and mice with experimental PH. RNA sequencing of BM-derived PACs showed that 5-HT antagonism significantly altered biologic pathways regulating cell proliferation, locomotion and migration, and cytokine production and response to cytokine stimulus.
CONCLUSIONS - Together, our findings illustrate that BM-derived PACs directly contribute to experimental PH with SU5416-enhanced endovascular injury by mediating small-vessel stiffening and remodeling in a 5-HT signaling-dependent manner.
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14 MeSH Terms
Adrenal serotonin derives from accumulation by the antidepressant-sensitive serotonin transporter.
Brindley RL, Bauer MB, Walker LA, Quinlan MA, Carneiro AMD, Sze JY, Blakely RD, Currie KPM
(2019) Pharmacol Res 140: 56-66
MeSH Terms: Adrenal Glands, Animals, Antidepressive Agents, Female, Male, Mesencephalon, Mice, Transgenic, Models, Animal, Rhombencephalon, Serotonin, Serotonin Plasma Membrane Transport Proteins, Spinal Cord, Tyrosine 3-Monooxygenase
Show Abstract · Added August 8, 2018
Adrenal chromaffin cells comprise the neuroendocrine arm of the sympathetic nervous system and secrete catecholamines to coordinate the appropriate stress response. Deletion of the serotonin (5-HT) transporter (SERT) gene in mice (SERT mice) or pharmacological block of SERT function in rodents and humans augments this sympathoadrenal stress response (epinephrine secretion). The prevailing assumption is that loss of CNS SERT alters central drive to the peripheral sympathetic nervous system. Adrenal chromaffin cells also prominently express SERT where it might coordinate accumulation of 5-HT for reuse in the autocrine control of stress-evoked catecholamine secretion. To help test this hypothesis, we have generated a novel mouse model with selective excision of SERT in the peripheral sympathetic nervous system (SERT), generated by crossing floxed SERT mice with tyrosine hydroxylase Cre driver mice. SERT expression, assessed by western blot, was abolished in the adrenal gland but not perturbed in the CNS of SERT mice. SERT-mediated [H] 5-HT uptake was unaltered in midbrain, hindbrain, and spinal cord synaptosomes, confirming transporter function was intact in the CNS. Endogenous midbrain and whole blood 5-HT homeostasis was unperturbed in SERT mice, contrasting with the depleted 5-HT content in SERT mice. Selective SERT excision reduced adrenal gland 5-HT content by ≈ 50% in SERT mice but had no effect on adrenal catecholamine content. This novel model confirms that SERT expressed in adrenal chromaffin cells is essential for maintaining wild-type levels of 5-HT and provides a powerful tool to help dissect the role of SERT in the sympathetic stress response.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging.
Ellegood J, Yee Y, Kerr TM, Muller CL, Blakely RD, Henkelman RM, Veenstra-VanderWeele J, Lerch JP
(2018) Mol Autism 9: 24
MeSH Terms: Animals, Brain, Female, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mutation, Neurons, Serotonin, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added May 4, 2018
Background - The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, , has been extensively studied.
Methods - Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an knockout mouse on a C57BL/6 genetic background, along with an Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6).
Results - Individually (same sex, same background, same genotype), the only differences found were in the female knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices.
Conclusions - This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization.
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11 MeSH Terms
Upregulation of SERT and ADORA1 in broilers with acute right ventricular failure.
Kamely M, Karimi Torshizi MA, Wideman RF, West J
(2019) Res Vet Sci 125: 397-400
MeSH Terms: Animals, Chickens, Cyclic Nucleotide Phosphodiesterases, Type 5, Gene Expression Regulation, Heart Failure, Hypertension, Pulmonary, Male, Myocardium, Poultry Diseases, Receptor, Adenosine A1, Serotonin Plasma Membrane Transport Proteins, Troponin T, Up-Regulation
Show Abstract · Added April 2, 2019
Pulmonary hypertension (PH), remains a challenging disease with a large impact on both humans and meat-type chickens. PH is characterized by the onset of idiopathic pulmonary arterial hypertension leading to right ventricular failure. In this experiment relative gene expression of adenosine A receptor (ADORA1), serotonin transporter (SERT), phosphodiesterase 5A (PDE5) and troponin T2 were compared in hearts from broilers with acute right ventricular failure and from healthy birds. There were major increases in adenosine A receptor (177%) and serotonin transporter (475%), and more modest but significant increases in PDE5 (146%) and troponin T2 (140%) gene expressions in broilers with right ventricular failure compared to healthy birds (P<0.01). This novel report shows that pulmonary hypertension related gene expression in broilers is similar to that in humans. This molecular similarity between PH in broilers and human patients suggests, first, that they will make a suitable animal model for study PH in humans, but also that the literature on PH in humans may be profitably applied to the study of PH in broilers.
Copyright © 2017. Published by Elsevier Ltd.
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13 MeSH Terms
The Gain-of-Function Integrin β3 Pro33 Variant Alters the Serotonin System in the Mouse Brain.
Dohn MR, Kooker CG, Bastarache L, Jessen T, Rinaldi C, Varney S, Mazalouskas MD, Pan H, Oliver KH, Velez Edwards DR, Sutcliffe JS, Denny JC, Carneiro AMD
(2017) J Neurosci 37: 11271-11284
MeSH Terms: Animals, Brain, Female, Gain of Function Mutation, Gene Knock-In Techniques, Genetic Variation, Humans, Integrin beta3, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Proline, Protein Binding, Serotonin, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added November 2, 2017
Engagement of integrins by the extracellular matrix initiates signaling cascades that drive a variety of cellular functions, including neuronal migration and axonal pathfinding in the brain. Multiple lines of evidence link the gene encoding the integrin β3 subunit with the serotonin (5-HT) system, likely via its modulation of the 5-HT transporter (SERT). The coding polymorphism Leu33Pro (rs5918, Pl) produces hyperactive αvβ3 receptors that influence whole-blood 5-HT levels and may influence the risk for autism spectrum disorder (ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant, male-specific associations between the Pro33 allele and attention-deficit hyperactivity disorder and ASDs. Here, we used knock-in (KI) mice expressing an variant that phenocopies the human Pro33 variant to elucidate the consequences of constitutively enhanced αvβ3 signaling to the 5-HT system in the brain. KI mice displayed deficits in multiple behaviors, including anxiety, repetitive, and social behaviors. Anatomical studies revealed a significant decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT activity and reduced localization of SERTs to integrin adhesion complexes in synapses of KI mice. Inhibition of focal adhesion kinase (FAK) rescued SERT function in synapses of KI mice, demonstrating that constitutive active FAK signaling downstream of the Pro32Pro33 integrin αvβ3 suppresses SERT activity. Our studies identify a complex regulation of 5-HT homeostasis and behaviors by integrin αvβ3, revealing an important role for integrins in modulating risk for neuropsychiatric disorders. The integrin β3 Leu33Pro coding polymorphism has been associated with autism spectrum disorders (ASDs) within a subgroup of patients with elevated blood 5-HT levels, linking integrin β3, 5-HT, and ASD risk. We capitalized on these interactions to demonstrate that the Pro33 coding variation in the murine integrin β3 recapitulates the sex-dependent neurochemical and behavioral attributes of ASD. Using state-of-the-art techniques, we show that presynaptic 5-HT function is altered in these mice, and that the localization of 5-HT transporters to specific compartments within the synapse, disrupted by the integrin β3 Pro33 mutation, is critical for appropriate reuptake of 5-HT. Our studies provide fundamental insight into the genetic network regulating 5-HT neurotransmission in the CNS that is also associated with ASD risk.
Copyright © 2017 the authors 0270-6474/17/3711272-14$15.00/0.
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16 MeSH Terms