Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Israelyan, Narek; Anderson, George M.; Snyder, Isaac; Veenstra‐VanderWeele, Jeremy; Blakely, Randy D.; Gershon, Michael D.

doi:10.1172/jci84877

Cited by 116 publications

(149 citation statements)

References 76 publications

(93 reference statements)

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“…In contrast, other studies have found that some mutations in the SERT gene cause a gain-of-function leading to increased SERT expression 38. Serotonin transporter is responsible for the termination of serotonin action within the brain,19 and thus, increased expression of the SERT gene may reduce the effect of serotonin inside the brain.…”

Section: Discussionmentioning

confidence: 92%

Serotonin and serotonin transporter levels in autistic children

Abdulamir

Abdul‐Rasheed

Abdulghani

2018

SMJ

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ObjectivesTo assess the possible correlation between serotonin and serotonin transporter (SERT) with the autism severity and investigate the association between these parameters in autistic children to assess their possible role for diagnosis of autism severity.MethodsA comparative cross-sectional study was carried out in the Chemistry and Biochemistry Department, College of Medicine, Al-Nahrain University, Baghdad, Iraq while the samples were taken from 60 male autistic children recruited to the Department of Pediatrics at Al-Sader Hospital, Baghdad, Iraq between November 2014 amd April 2015. Levels of serotonin and serotonin transporters (SERT) were determined in 60 male autistic Iraqi patients classified into mild, moderate and severe (20 for each). These levels were compared with those of 26 healthy control children.ResultsLevels of serotonin and SERT were significantly increased in autistic children than that of gender and age-matched controls. Serotonin levels were 80.63± 21.83 ng/ml in mild, 100.39±23.07 ng/ml moderate, and 188.7±31.72 ng/ml severe autistic patients. Serotonin transporter levels were 10.13±4.51 ng/ml in mild, 13.15±4.71 ng/ml moderate, and 16.32±6.7 ng/ml in severe autistic patients. The increase of both serotonin and SERT levels were associated with severity of autism. Receiver operating characteristic (ROC) analysis can be used for diagnostic and prognostic purposes.ConclusionsHigh serotonin and SERT levels may indicate that these biomarkers have a role in the autism pathogenesis and support the possibility of using serotonin and SERT to diagnose autism severity.

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Section: Discussionmentioning

confidence: 92%

Serotonin and serotonin transporter levels in autistic children

Abdulamir

Abdul‐Rasheed

Abdulghani

2018

SMJ

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“…When measured separately, enteric glial elimination did not alter the rates of gastric emptying or small intestinal transit (Figure 6D–E), suggesting that the effects of enteric glial elimination are most prominent in the colon. We therefore examined colonic motility in more detail and excluded the effects of extrinsic nerves by studying the propagation of colonic migrating motor complexes (CMMCs; an ENS-dependent manifestation of the peristaltic reflex) in an ex vivo preparation 15, 26 . Colons were isolated from Cre − and Cre + mice, suspended in oxygenated Krebs solution and perfused through the lumen at an intraluminal pressure sufficient to induce CMMCs.…”

Section: Resultsmentioning

confidence: 99%

“…Total gastrointestinal transit time, gastric emptying, colonic motility , and small intestinal transit were measured as previously described 15 . Small intestinal transit was estimated by the position of the geometric center of rhodamine-dextran 15 minutes after gavage 16 ; values are distributed between 1 (minimal motility) and 10 (maximal motility).…”

Section: Methodsmentioning

confidence: 99%

Enteric Glia Regulate Gastrointestinal Motility but Are Not Required for Maintenance of the Epithelium in Mice

et al. 2017

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Background & Aims When the glial fibrillary acidic protein (GFAP) promoter is used to express cellular toxins that eliminate glia in mice, intestinal epithelial permeability and proliferation increase; this led to the concept that glia are required for maintenance of the gastrointestinal epithelium. Many enteric glia, however, particularly in the mucosa, do not express GFAP. In contrast, virtually all enteric glia express proteolipid protein 1 (PLP1). We investigated whether elimination of PLP1-expressing cells compromises epithelial maintenance or gastrointestinal motility. Methods We generated mice that express tamoxifen-inducible Cre recombinase under control of the Plp1 promoter and carry the diptheria toxin subunit A (DTA) transgene in the Rosa26 locus (Plp1CreER;Rosa26DTA mice). In these mice, PLP1-expressing glia are selectively eliminated without affecting neighboring cells. We measured epithelial barrier function and gastrointestinal motility in these mice and littermate controls, and analyzed epithelial cell proliferation and ultrastructure from their intestinal tissues. To compare our findings with those from previous studies, we also eliminated glia with ganciclovir in GfapHSV-TK mice. Results Expression of DTA in PLP1-expressing cells selectively eliminated enteric glia from the small and large intestines, but caused no defects in epithelial proliferation, barrier integrity, or ultrastructure. In contrast, administration of ganciclovir to GfapHSV-TK mice eliminated fewer glia but caused considerable non-glial toxicity and epithelial cell death. Elimination of PLP1-expressing cells did not reduce survival of neurons in the intestine, but altered gastrointestinal motility in female, but not male, mice. Conclusions Using the Plp1 promoter to selectively eliminate glia in mice, we found that enteric glia are not required for maintenance of the intestinal epithelium but are required for regulation of intestinal motility in females. Previous observations supporting the concept that maintenance of the intestinal epithelium requires enteric glia can be attributed to non-glial toxicity in GfapHSV-TK mice and epithelial-cell expression of GFAP. Contrary to widespread notions, enteric glia are therefore not required for epithelial homeostasis. However, they regulate intestinal motility in a sex-dependent manner.

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“…These functions, however, are not simply accomplished, but require enteric motility and management by the nervous system. In addition to its well-known roles in controlling gastrointestinal motility and secretion, the nervous system regulates mucosal epithelial growth, 1,2 as well as gastrointestinal manifestations of immunity and inflammation. 3,4 Although the gut has long been known to be able to function independently of input from the central nervous system [CNS], 5 it cannot function independently of input from its intrinsic enteric nervous system [ENS]; a lethal pseudo-obstruction occurs when even a small segment of bowel is aganglionic.…”

mentioning

confidence: 99%

“…There has been relatively little investigation of the effects of ENS hypoplasia or hyperplasia in the human intestine, although both are functionally deleterious when either is genetically induced in mice. 2,4,11–15 Hyperplasia and hypoplasia of the human ENS, moreover, are known to occur and both are associated with dysmotility. Examples of ENS hyperplasia are intestinal ganglioneuromatosis, which occurs in association with neurofibromatosis type 1 and multiple endocrine neoplasia 2B, 16–18 and intestinal neuronal dysplasia type B, which involves hyperplastic ganglia in the submucosa.…”

mentioning

confidence: 99%