Neuropeptide s receptor induces neuropeptide expression and associates with intermediate phenotypes of functional gastrointestinal disorders (gastroenterology 2010;138:98-107).
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ABSTRACT:
SUBMITTER: Kang JM
PROVIDER: S-EPMC2879859 | biostudies-literature | 2010 Apr
REPOSITORIES: biostudies-literature
Publications
Neuropeptide s receptor induces neuropeptide expression and associates with intermediate phenotypes of functional gastrointestinal disorders (gastroenterology 2010;138:98-107).
Journal of neurogastroenterology and motility 20100428 2
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Project description:Background & aimsNPSR1, the receptor for neuropeptide S (NPS), is expressed by gastrointestinal (GI) enteroendocrine cells, and is involved in inflammation, anxiety, and nociception. NPSR1 polymorphisms are associated with asthma and inflammatory bowel disease. We aimed to determine whether NPS induces expression of GI neuropeptides; and to associate NPSR1 single nucleotide polymorphisms (SNPs) with symptom phenotype and GI functions in health and functional GI disorders (FGID).MethodsThe effect of NPS on messenger RNA expression of neuropeptides was assessed using real-time polymerase chain reaction in NPSR1-tranfected HEK293 cells. Seventeen NPSR1 SNPs were successfully genotyped in 699 subjects from a regional cohort of 466 FGID patients and 233 healthy controls. Associations were sought using gender-adjusted regression analysis and false discovery rate correction.ResultsNPS-NPSR1 signaling induced increased expression of cholecystokinin, vasoactive intestinal peptide, peptide YY, and somatostatin. There were no significant associations with phenotypes of FGID symptoms. There were several NPSR1 SNPs associated with individual motor or sensory functions; the associations of SNPs rs2609234, rs6972158, and rs1379928 with colonic transit rate remained significant after false discovery rate correction. The rs1379928 polymorphism was also associated with pain, gas, and urgency sensory ratings at 36 mm Hg distention, the level prespecified for formal testing. Associations with rectal sensory ratings were not significant after false discovery rate correction.ConclusionsExpression of several neuropeptides is induced upon NPS-NPSR1 signaling; NPSR1 variants are associated with colonic transit in FGID. The role of the NPS system in FGID deserves further study.
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Project description:The small effect size of most individual risk factors for psychiatric disorders likely reflects biological heterogeneity and diagnostic imprecision, which has encouraged genetic studies of intermediate biological phenotypes that are closer to the molecular effects of risk genes than are the clinical symptoms. Neuroimaging-based intermediate phenotypes have emerged as particularly promising because they map risk associated gene effects onto physiological processes in brain that are altered in patients and in their healthy relatives. Recent evidence using this approach has elucidated discrete, dissociable biological mechanisms of risk genes at the level of neural circuitries, and their related cognitive functions. This approach may greatly contribute to our understanding of the genetics and pathophysiology of psychiatric disorders.
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Project description:Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes (IPs) that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI) is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA, ZNF804A, and APOE, may be higher for IPs characterized at the level of distributed neural systems than at the level of spatially localized brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of the human connectome.
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Project description:Functional gastrointestinal disorders (FGIDs) are common in the community. Many patients will consult a physician in primary care, but the burden that these diseases represent to secondary care has not been studied for many years. We therefore examined this subject.Unselected consecutive new adult patient referrals were recruited during a 3-year period from January 2010 until December 2012. Medical records were reviewed retrospectively and the following data were recorded: age and sex of the patient, symptoms reported or signs noted at the first consultation, all investigations requested and ultimate diagnosis after investigation to the level deemed appropriate by the consulting physician.A luminal gastroenterology clinic at a teaching hospital.There were a total of 613 new patient referrals (mean age 54.2 years, 357 (58.2%) female). In total, 214 (34.9%) patients were diagnosed as having an FGID. Among the 214 patients diagnosed with an FGID, 65.9% were female, compared with 54.1% without an FGID (p=0.005). Mean age of those with an FGID was 47.9 years, compared with 57.5 years among those without (p<0.001). The total number of symptoms reported was significantly higher among patients with an FGID, but the total number of investigations did not differ.More than one-third of new patient referrals to a luminal gastroenterology clinic were diagnosed with an FGID. These conditions form a large part of the workload in secondary care gastroenterology, and primary care commissioning needs to reflect this.
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Project description:Background and aimsFunctional gastrointestinal disorders (FGDs) are multifactorial disorders of the gut-brain interaction. This study investigated the prevalence of Axis I and spectrum disorders in patients with FGD and established the link between FGDs and psychopathological dimensions.MethodsA total of 135 consecutive patients with FGD were enrolled. The symptoms' severity was evaluated using questionnaires, while the psychiatric evaluation by clinical interviews established the presence/absence of mental (Diagnostic and Statistical Manual-4th edition, Axis I Diagnosis) or spectrum disorders.ResultsOf the 135 patients, 42 (32.3%) had functional dyspepsia, 52 (40.0%) had irritable bowel syndrome, 21 (16.2%) had functional bloating, and 20 (15.4%) had functional constipation. At least one psychiatric disorder was present in 46.9% of the patients, while a suprathreshold panic spectrum was present in 26.2%. Functional constipation was associated with depressive disorders (p < 0.05), while functional dyspepsia was related to the current major depressive episode (p < 0.05). Obsessive-compulsive spectrum was correlated with the presence of functional constipation and irritable bowel syndrome (p < 0.05).ConclusionThe high prevalence of subthreshold psychiatric symptomatology in patients with FGD, which is likely to influence the expression of gastrointestinal symptoms, suggested the usefulness of psychological evaluation in patients with FGDs.
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Project description:Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.
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Project description:HIV-associated neurocognitive disorders (HAND) describe a spectrum of neuropsychological impairment caused by HIV-1 infection. While the sequence of cellular and physiological events that lead to HAND remains obscure, it likely involves chronic neuroinflammation. Host genetic markers that increase the risk for HAND have been reported, but replication of such studies is lacking, possibly due to inconsistent application of a behavioral phenotype across studies. In the current study, we used histopathologic phenotypes in order to validate putative risk alleles for HAND. The National NeuroAIDS Tissue Consortium, a longitudinal study of the neurologic manifestations of HIV. Data and specimens were obtained from 175 HIV-infected adults. After determining several potential covariates of neurocognitive functioning, we quantified levels of six histopathological markers in the frontal lobe in association with neurocognitive functioning: SYP, MAP 2, HLA-DR, Iba1, GFAP, and β-amyloid. We then determined alleles of 15 candidate genes for their associations with neurocognitive functioning and histopathological markers. Finally, we identified the most plausible causal pathway based on our data using a multi-stage linear regression-based mediation analysis approach. None of the genetic markers were associated with neurocognitive functioning. Of the histopathological markers, only MAP 2 and SYP were associated with neurocognitive functioning; however, MAP 2 and SYP did not vary as a function of genotype. Mediation analysis suggests a causal pathway in which presynaptic degeneration (SYP) leads to somatodendritic degeneration (MAP 2) and ultimately neurocognitive impairment. This study did not support the role of host genotype in the histopathology underlying HAND. The findings lend further support for synaptodendritic degeneration as the proximal underlying neuropathological substrate of HAND.
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Project description:BackgroundThe expansion of GGC repeats (typically exceeding 60 repeats) in the 5' untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson's disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored.MethodsHere, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs.ResultsOur findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG, were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex.ConclusionsOur in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs.
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