Pitt-Hopkins Mouse Model has Altered Particular Gastrointestinal Transits In Vivo.
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TLDR
The assessment of gut transit indicates that, while whole‐gut transit velocity was similar between the groups, the upper GI and distal colon transit velocities were significantly reduced in the PTHS mice, which is the first evidence of specific gut related problems in the Heterozygous TCF4 functional knockout mice.Abstract:
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder, classified as an autism spectrum disorder that is caused by the haploinsufficiency of Transcription Factor 4 (TCF4). The most common non-neurological symptoms in PTHS patients are gastrointestinal (GI) disturbances, mainly gastroesophageal reflux and severe constipation (in about 30 and 75% of PTHS patients, respectively). We hypothesized that the recently recognized mouse model of PTHS will exhibit problems with their gut function. We conducted series of in vivo tests on 15- to 19- week old male mice, heterozygous for the TCF4 functional deletion, mimicking the TCF4 haploinsufficiency in PTHS patients, and their wild type littermates. Data collection and initial analysis were performed blindly, that is, the genotyping key was received after the mean values were calculated for each individual animal, and then mean/median of each group was subsequently calculated. Body weight, fecal pellet output, and fluid content were similar between the groups, indicating normal gross growth of PTHS mice and their overall physiological GI motility and intestinal secretion/absorption. There were no significant differences in gut length and gross appearance pointing out that PTHS mice have normal gut in gross anatomical terms. However, the assessment of gut transit indicates that, while whole-gut transit velocity was similar between the groups, the upper GI and distal colon transit velocities were significantly reduced in the PTHS mice. This is the first evidence of specific gut related problems in the PTHS mice. Our study also validates the TCF4 functional knockout mice as an animal model to study PTHS-associated GI disturbances.read more
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The bowel and beyond: the enteric nervous system in neurological disorders
Meenakshi Rao,Michael D. Gershon +1 more
TL;DR: Evidence for ENS dysfunction is reviewed in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease, and animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions.
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Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function
Andrew J. Kennedy,Andrew J. Kennedy,Elizabeth J. Rahn,Brynna S. Paulukaitis,Brynna S. Paulukaitis,Katherine E. Savell,Holly B. Kordasiewicz,Jing Wang,John W. Lewis,Jessica L. Posey,Sarah K. Strange,Mikael C. Guzman-Karlsson,Scott E. Phillips,Kyle Decker,S. Timothy Motley,Eric E. Swayze,David J. Ecker,Todd P. Michael,Jeremy J. Day,J. David Sweatt,J. David Sweatt +20 more
TL;DR: It is demonstrated that Tcf4 haploinsufficiency mice have deficits in social interaction, ultrasonic vocalization, prepulse inhibition, and spatial and associative learning and memory, and it is observed that Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits in T cf4(+/-) mice.
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Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1
Matthew D. Rannals,Gregory R. Hamersky,Stephanie Cerceo Page,Morganne N. Campbell,Aaron Briley,Ryan A A. Gallo,BaDoi N. Phan,Thomas M. Hyde,Joel E. Kleinman,Joo Ho Shin,Andrew E. Jaffe,Daniel R. Weinberger,Brady J. Maher +12 more
TL;DR: This work identifies TCF4 as a regulator of neuronal intrinsic excitability in part by repression of Kcnq1 and Scn10a and suggests that this molecular function may underlie pathophysiology associated with neuropsychiatric disorders.
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Agonist-Evoked Ca2+ Signaling in Enteric Glia Drives Neural Programs That Regulate Intestinal Motility in Mice
TL;DR: Glial excitability encoded by intracellular Ca2+ signaling functions to modulate excitatory enteric circuits to improve gut function in motility disorders.
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Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons.
Matthias Jung,Benjamin M. Häberle,Tristan Tschaikowsky,Marie-Theres Wittmann,Elli-Anna Balta,Vivien-Charlott Stadler,Christiane Zweier,Arnd Dörfler,Christian Johannes Gloeckner,Christian Johannes Gloeckner,D. Chichung Lie +10 more
TL;DR: The data suggest that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved, and validate Tcf4-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS.
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