Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression.

BACKGROUND & AIMS: Mood disorders and constipation are often comorbid, yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Therefore, defects in neuron production of 5-HT might result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%-80% decrease in levels of 5-HT in the central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. METHODS: We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice, and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT-dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamine-evoked release of endogenous 5-HT. In live mice, we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximodistal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. RESULTS: Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls, and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth CONCLUSIONS: In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.

Upregulated function of mitochondria-associated ER membranes in Alzheimer disease.

Alzheimer disease (AD) is associated with aberrant processing of the amyloid precursor protein (APP) by γ-secretase, via an unknown mechanism. We recently showed that presenilin-1 and -2, the catalytic components of γ-secretase, and γ-secretase activity itself, are highly enriched in a subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAMs). We now show that MAM function and ER-mitochondrial communication-as measured by cholesteryl ester and phospholipid synthesis, respectively-are increased significantly in presenilin-mutant cells and in fibroblasts from patients with both the familial and sporadic forms of AD. We also show that MAM is an intracellular detergent-resistant lipid raft (LR)-like domain, consistent with the known presence of presenilins and γ-secretase activity in rafts. These findings may help explain not only the aberrant APP processing but also a number of other biochemical features of AD, including altered lipid metabolism and calcium homeostasis. We propose that upregulated MAM function at the ER-mitochondrial interface, and increased cross-talk between these two organelles, may play a hitherto unrecognized role in the pathogenesis of AD.

Gastrointestinal Issues and Autism Spectrum Disorder.

Gastrointestinal disorders are one of the most common medical conditions that are comorbid with autism spectrum disorders. These comorbidities can cause greater severity in autism spectrum disorder symptoms, other associated clinical manifestations, and lower quality of life if left untreated. Clinicians need to understand how these gastrointestinal issues present and apply effective therapies. Effective treatment of gastrointestinal problems in autism spectrum disorder may result in marked improvements in autism spectrum disorder behavioral outcomes. This article discusses the gastrointestinal disorders commonly associated with autism spectrum disorders, how they present, and studied risk factors.

Gastrointestinal Issues and Autism Spectrum Disorder.

Gastrointestinal disorders are one of the most common medical conditions that are comorbid with autism spectrum disorders. These comorbidities can cause greater severity in autism spectrum disorder symptoms, other associated clinical manifestations, and lower quality of life if left untreated. Clinicians need to understand how these gastrointestinal issues present and apply effective therapies. Effective treatment of gastrointestinal problems in autism spectrum disorder may result in marked improvements in autism spectrum disorder behavioral outcomes. This article discusses the gastrointestinal disorders commonly associated with autism spectrum disorders, how they present, and studied risk factors.

Niemann-Pick type C pathogenesis and treatment: from statins to sugars.

The isolation of the causative genes for Niemann-Pick type C disease, a panethnic lysosomal lipid storage disorder, has provided models of how sterols and other lipids such as glycosphingolipids traverse the membranes of eukaryotic cells. Unfortunately, these molecular advances have yet to reciprocate with a cure for this devastating neurodegenerative disorder where neuronal replenishment will most likely yield the greatest benefit. In the meantime, stabilizing treatment strategies based on the removal of presumably toxic metabolites are in place. For example, the small molecule inhibition of glucosylceramide synthase by miglustat limits ganglioside accumulation and is now the only approved treatment of Niemann-Pick type C. In addition, 2-hydroxypropyl-B-cyclodextrin, a lipid chelator, relieves the lysosomal to endoplasmic reticulum blockage and markedly increases the life expectancy of the murine model. Ultimately, these strategies, targeting the primary biochemical lesion in these cells, and others will likely be combined to provide a synergistic cocktail approach to treating this disease.