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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
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
Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response.
Brindley RL, Bauer MB, Blakely RD, Currie KPM
(2017) ACS Chem Neurosci 8: 943-954
MeSH Terms: Adrenal Medulla, Animals, Arousal, Chromaffin Cells, Humans, Serotonin, Serotonin Plasma Membrane Transport Proteins, Stress, Physiological, Sympathetic Nervous System, Synaptic Transmission
Show Abstract · Added May 3, 2017
Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. Experimentally, loss of SERT function (SERT knockout mice or chronic pharmacological block) has been reported to augment the sympathetic stress response. Alterations to serotonergic signaling in the CNS and thus central drive to the peripheral sympathetic nervous system are presumed to underlie this augmentation. Although less widely recognized, SERT is robustly expressed in chromaffin cells of the adrenal medulla, the neuroendocrine arm of the sympathetic nervous system. Adrenal chromaffin cells do not synthesize 5-HT but accumulate small amounts by SERT-mediated uptake. Recent evidence demonstrated that 5-HT receptors inhibit catecholamine secretion from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability or voltage-gated Ca channels. This raises the possibility that the adrenal medulla is a previously unrecognized peripheral hub for serotonergic control of the sympathetic stress response. As a framework for future investigation, a model is proposed in which stress-evoked adrenal catecholamine secretion is fine-tuned by SERT-modulated autocrine 5-HT signaling.
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10 MeSH Terms
An autism-associated serotonin transporter variant disrupts multisensory processing.
Siemann JK, Muller CL, Forsberg CG, Blakely RD, Veenstra-VanderWeele J, Wallace MT
(2017) Transl Psychiatry 7: e1067
MeSH Terms: Acoustic Stimulation, Animals, Auditory Perception, Autism Spectrum Disorder, Autistic Disorder, Behavior, Animal, Cognition, Genetic Variation, Learning, Mice, Mutation, Photic Stimulation, Serotonin Plasma Membrane Transport Proteins, Visual Perception
Show Abstract · Added August 31, 2018
Altered sensory processing is observed in many children with autism spectrum disorder (ASD), with growing evidence that these impairments extend to the integration of information across the different senses (that is, multisensory function). The serotonin system has an important role in sensory development and function, and alterations of serotonergic signaling have been suggested to have a role in ASD. A gain-of-function coding variant in the serotonin transporter (SERT) associates with sensory aversion in humans, and when expressed in mice produces traits associated with ASD, including disruptions in social and communicative function and repetitive behaviors. The current study set out to test whether these mice also exhibit changes in multisensory function when compared with wild-type (WT) animals on the same genetic background. Mice were trained to respond to auditory and visual stimuli independently before being tested under visual, auditory and paired audiovisual (multisensory) conditions. WT mice exhibited significant gains in response accuracy under audiovisual conditions. In contrast, although the SERT mutant animals learned the auditory and visual tasks comparably to WT littermates, they failed to show behavioral gains under multisensory conditions. We believe these results provide the first behavioral evidence of multisensory deficits in a genetic mouse model related to ASD and implicate the serotonin system in multisensory processing and in the multisensory changes seen in ASD.
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Serotonin Transporter-Independent Actions of the Antidepressant Vortioxetine As Revealed Using the SERT Met172 Mouse.
Nackenoff AG, Simmler LD, Baganz NL, Pehrson AL, Sánchez C, Blakely RD
(2017) ACS Chem Neurosci 8: 1092-1100
MeSH Terms: Animals, Antidepressive Agents, Behavior, Animal, Depression, Disease Models, Animal, Hindlimb Suspension, Hippocampus, Mice, Neurogenesis, Piperazines, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sulfides, Synaptosomes, Vortioxetine
Show Abstract · Added August 31, 2018
Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets. At therapeutic doses, vortioxetine interacts with SERT as well as 5-HT, 5-HT, 5-HT, and 5-HT receptors. We assessed the SERT-dependency of vortioxetine action using the SERT Met172 mouse model, which disrupts high-affinity interactions of many antidepressants with the transporter. We demonstrate that the SERT Met172 substitution induces an ∼19-fold loss in vortioxetine potency for SERT inhibition in midbrain synaptosomes. Moreover, in these mice, we observed reduced SERT occupancy, a diminished ability to prolong 5-HT clearance, and a reduced capacity to elevate extracellular 5-HT. Despite reduced interactions with SERT, vortioxetine maintained its ability to enhance mobility in tail suspension and forced swim tests, reduce consumption latency in the novelty induced hypophagia test, and promoted proliferation and survival of subgranular zone hippocampal stem cells. Our findings suggest that the antidepressant actions of vortioxetine may be SERT-independent, and encourage consideration of agents that mimic one or more actions of the drug in the development of improved depression treatments.
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15 MeSH Terms
Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment.
Muller CL, Anacker AM, Rogers TD, Goeden N, Keller EH, Forsberg CG, Kerr TM, Wender C, Anderson GM, Stanwood GD, Blakely RD, Bonnin A, Veenstra-VanderWeele J
(2017) Neuropsychopharmacology 42: 427-436
MeSH Terms: Animals, Female, Genotype, Maternal-Fetal Exchange, Mice, Inbred Strains, Mice, Transgenic, Placenta, Pregnancy, Prosencephalon, Rhombencephalon, Serotonin, Serotonin Plasma Membrane Transport Proteins, Thalamus
Show Abstract · Added August 31, 2018
Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment.
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MeSH Terms
An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells.
Brindley RL, Bauer MB, Blakely RD, Currie KPM
(2016) Neuropharmacology 110: 438-448
MeSH Terms: Adrenal Glands, Animals, Calcium, Calcium Channels, N-Type, Cations, Divalent, Cells, Cultured, Chromaffin Cells, Exocytosis, Male, Membrane Potentials, Mice, Inbred C57BL, Mice, Knockout, Potassium Channels, Voltage-Gated, Receptors, Serotonin, Serotonin, Serotonin Agents, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added August 22, 2016
Adrenal chromaffin cells (ACCs), the neuroendocrine arm of the sympathetic nervous system, secrete catecholamines to mediate the physiological response to stress. Although ACCs do not synthesize 5-HT, they express the serotonin transporter (SERT). Genetic variations in SERT are linked to several CNS disorders but the role(s) of SERT/5-HT in ACCs has remained unclear. Adrenal glands from wild-type mice contained 5-HT at ≈ 750 fold lower abundance than adrenaline, and in SERT(-/-) mice this was reduced by ≈80% with no change in catecholamines. Carbon fibre amperometry showed that SERT modulated the ability of 5-HT1A receptors to inhibit exocytosis. 5-HT reduced the number of amperometric spikes (vesicular fusion events) evoked by KCl in SERT(-/-) cells and wild-type cells treated with escitalopram, a SERT antagonist. The 5-HT1A receptor antagonist WAY100635 blocked the inhibition by 5-HT which was mimicked by the 5-HT1A agonist 8-OH-DPAT but not the 5-HT1B agonist CP93129. There was no effect on voltage-gated Ca(2+) channels, K(+) channels, or intracellular [Ca(2+)] handling, showing the 5-HT receptors recruit an atypical inhibitory mechanism. Spike charge and kinetics were not altered by 5-HT receptors but were reduced in SERT(-/-) cells compared to wild-type cells. Our data reveal a novel role for SERT and suggest that adrenal chromaffin cells might be a previously unrecognized hub for serotonergic control of the sympathetic stress response.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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17 MeSH Terms
Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor.
Oliver KH, Duvernay MT, Hamm HE, Carneiro AM
(2016) J Biol Chem 291: 20210-9
MeSH Terms: Adenosine Diphosphate, Animals, Blood Platelets, Citalopram, Female, Male, Mice, Mice, Knockout, Platelet Glycoprotein GPIIb-IIIa Complex, Receptor, Serotonin, 5-HT2A, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added October 26, 2016
Reduced platelet aggregation and a mild bleeding phenotype have been observed in patients chronically taking selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear how SSRIs, which inhibit the plasma membrane serotonin transporter (SERT), modulate hemostasis. Here, we examine how sustained inhibition of SERT activity alters serotonergic signaling and influences platelet activation and hemostasis. Pharmaceutical blockade (citalopram dosing) or genetic ablation (SERT(-/-)) of SERT function in vivo led to reduced serotonin (5-hydroxytryptamine (5-HT)) blood levels that paralleled a mild bleeding phenotype in mice. Transfusion of wild-type platelets to SERT(-/-) mice normalized bleeding times to wild-type levels, suggesting that loss of SERTs causes a deficiency in platelet activation. Although SERT(-/-) platelets displayed no difference in P-selectin or αIIbβ3 activation upon stimulation with thrombin, ADP-mediated αIIbβ3 activation is reduced in SERT(-/-) platelets. Additionally, synergistic potentiation of αIIbβ3 activation by ADP and 5-HT is lost in SERT(-/-) platelets. Acute treatment of wild-type platelets with 5-HT2A receptor (5-HT2AR) antagonists or SSRIs revealed that functional 5-HT2ARs, not SERTs, are necessary for the synergistic activation of αIIbβ3 by dual 5-HT/ADP stimulation. Pharmacological studies using radiolabeled guanosine 5'-3-O-([(35)S]thio)triphosphate and [(3)H]ketanserin revealed that platelets isolated from SERT(-/-) or citalopram-treated mice have reduced activation of G-proteins coupled to 5-HT2ARs and receptor surface expression. Taken together, these data demonstrate that sustained SERT loss of function reduces 5-HT2AR surface expression that is critical for the synergistic activation of αIIbβ3 by 5-HT and ADP. These results highlight an antiplatelet strategy centered on blocking or desensitizing 5-HT2AR to attenuate ADP-mediated αIIbβ3 activation.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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11 MeSH Terms
Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.
Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely RD, Gershon MD
(2016) J Clin Invest 126: 2221-35
MeSH Terms: Animals, Autism Spectrum Disorder, Enteric Nervous System, Female, Gastrointestinal Motility, Gastrointestinal Tract, Genetic Variation, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Models, Animal, Neurogenesis, Pregnancy, Serotonin, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added August 31, 2018
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
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