Serotonin 6 receptor controls Alzheimer's disease and depression.
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ABSTRACT:
SUBMITTER: Yun HM
PROVIDER: S-EPMC4694947 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Given the failure to develop disease-modifying therapies for Alzheimer's disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.
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Project description:Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic serotonin receptor 3A (5-HT(3A)R) is specifically expressed in CGE-derived migrating interneurons and upregulated while they invade the developing cortex. Functional investigations using calcium imaging, electrophysiological recordings and migration assays indicate that CGE-derived INs increase their response to 5-HT(3A)R activation during the late phase of cortical plate invasion. Using genetic loss-of-function approaches and in vivo grafts, we further demonstrate that the 5-HT(3A)R is cell autonomously required for the migration and proper positioning of reelin-expressing CGE-derived INs in the neocortex. Our findings reveal a requirement for a serotonin receptor in controlling the migration and laminar positioning of a specific subtype of cortical IN.
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Project description:Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR) in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR) superfamily and is distantly related to serotonergic type 7 (5HT7) receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi) was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni.
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Project description:Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.
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Project description:mRNA for serotonin 2C receptor (5-HT(2C)R) undergoes editing which results in numerous isoforms. More highly edited isoforms exhibit decreased function. We recently found greater 5-HT(2C)R editing in suicide victims with prior bipolar disorder (BPD) or schizophrenia (SZ) compared with non-suicide patients and normal controls (NC). This study compares suicides and non-suicides with major depressive disorder (MDD(Suic) and MDD(NoSuic)) and non-suicide NC.mRNA editing was assessed in prefrontal cortex of 24 MDD(Suic), 21 MDD(NoSuic), and 56 NC using next generation sequencing. mRNA expression of 5-HT(2C)R and editing enzymes (ADAR1-2) was assessed by real-time PCR.Editing was lower in MDD(NoSuic) than in MDD(Suic), which did not differ from NC. No differences in the 5-HT(2C)R or ADAR1 expression were detected. ADAR2 expression was higher in NC than in MDD subjects, but did not differ between MDD(NoSuic) and MDD(Suic).Our findings suggest the presence of two factors associated with 5-HT(2C)R editing. One factor, which probably stems from decreased ADAR2 expression, is linked to MDD and is associated with less editing. The other, seen also in our previous study of suicide in BP and SZ, is linked to suicide alone and is associated with more editing and, therefore, less receptor function.
| S-EPMC4120662 | biostudies-literature
Project description:Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine receptor α3 subtype (GlyRα3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin receptor type 1A-specific (5-HTR1A-specific) modulation directly induced dephosphorylation of GlyRα3 receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyRα3. The 5-HTR1A-GlyRα3 signaling pathway was distinct from opioid receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyRα3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A-GlyRα3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction.
| S-EPMC2964980 | biostudies-literature
Project description:Multiple lines of evidence suggest that serotonin type 1A (5-HT(1A)) receptor dysfunction is involved in the pathophysiology of mood disorders, and that alterations in 5-HT(1A) receptor function play a role in the mechanisms of antidepressant and mood stabilizer treatment. The literature is in disagreement, however, as to whether 5-HT(1A) receptor binding abnormalities exist in bipolar disorder (BD). We acquired PET images of 5-HT(1A) receptor binding in 26 unmedicated BD subjects and 37 healthy controls using [¹?F]FCWAY, a highly selective 5-HT(1A) receptor radio-ligand. The mean 5-HT(1A) receptor binding potential (BP(P)) was significantly lower in BD subjects compared to controls in cortical regions where 5-HT(1A) receptors are expressed post-synaptically, most prominently in the mesiotemporal cortex. Post-hoc assessments involving other receptor specific binding parameters suggested that this difference particularly affected the females with BD. The mean BPP did not differ between groups in the raphe nucleus, however, where 5-HT(1A) receptors are predominantly expressed pre-synaptically. Across subjects the BPP in the mesiotemporal cortex was inversely correlated with trough plasma cortisol levels, consistent with preclinical literature indicating that hippocampal 5-HT(1A) receptor expression is inhibited by glucocorticoid receptor stimulation. These findings suggest that 5-HT(1A) receptor binding is abnormally reduced in BD, and this abnormality may particularly involve the postsynaptic 5-HT(1A) receptor system of individuals with a tendency toward cortisol hypersecretion.
| S-EPMC3748207 | biostudies-literature
Project description:Abnormal serotonin type 1A (5-HT1A) receptor function and binding have been implicated in the pathophysiology of mood disorders. Preclinical studies have consistently shown that stress decreases the gene expression of 5-HT1A receptors in experimental animals, and that the associated increase in hormone secretion plays a crucial role in mediating this effect. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus. Lithium has further been shown to enhance 5-HT1A receptor function. To assess whether these effects translate to human subject with bipolar disorder (BD), positron emission tomography (PET) and [18F]trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N-(2-pyridyl) cyclohexanecarboxamide ([(18)F]FCWAY) were used to acquire PET images of 5-HT1A receptor binding in 10 subjects with BD, before and after treatment with lithium or divalproex. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala). When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action.
| S-EPMC3784836 | biostudies-literature
Project description:ObjectiveDepression in patients with cardiovascular disease is associated with increased risk of adverse clinical outcomes. Investigators have searched for potential biobehavioral explanations for this increased risk. Platelet activation and response to serotonin is an attractive potential mechanism. The aim of the study was to examine platelet serotonin signaling in a group of patients with coronary artery disease (CAD) and comorbid depression to define the relationship between platelet serotonin signaling and cardiovascular complications.MethodsA total of 300 patients with CAD were enrolled (145 with acute coronary syndrome and 155 with stable CAD). Depression was assessed using the Structured Clinical Interview for DSM-IV as well as Beck Depression Inventory II in a dichotomous and continuous manner. Platelet serotonin response was measured by serotonin augmented aggregation, direct platelet serotonin activation, platelet serotonin receptor density, and platelet serotonin uptake. Cardiovascular outcomes were assessed at 12-month follow-up.ResultsOne third of enrolled participants had at least minimal depressive symptoms and 13.6% had major depressive disorder. Depressed cardiovascular patients had significantly higher incidence of major (odds ratio = 3.43, 95% confidence interval = 1.49-7.91, p = .004) and minor (odds ratio = 2.42, 95% confidence interval = 1.41-4.13, p = .001) adverse cardiac events. Platelet serotonin response was not significantly different in patients with depression. Participants with major depressive disorder had higher serotonin receptor density (997.5 ± 840.8 vs 619.3 ± 744.3 fmol/ug, p = .009) primarily found in ACS patients. Depressed patients with minor adverse cardiac events had increased platelet response to serotonin.ConclusionsDepressed cardiovascular patients had higher serotonin receptor density and significantly higher incidence of major and minor cardiac adverse events. Future studies with larger sample sizes including patients with more severe depression are needed to expand on the present hypothesis-generating findings.
| S-EPMC6499626 | biostudies-literature