GABAA Receptor Subtypes Regulate Stress-Induced Colon Inflammation in Mice

Seifi, Mohsen; Rodaway, Scott; Rudolph, Uwe; Swinny, Jerome D.

doi:10.1053/j.gastro.2018.05.033

Cited by 42 publications

(30 citation statements)

References 39 publications

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“…; Seifi et al . ), it is important to note that GABA receptor activation in the colon may also be associated with deleterious side‐effects. Consistent with this suggestion, a recent study shows that activation of GABA A receptors in colon epithelium exacerbates acute colitis (Ma et al .…”

Section: Discussionmentioning

confidence: 99%

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Loeza‐Alcocer

McPherson

Gold

2019

The Journal of Physiology

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Key pointsr While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body.r Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability.r GABA A and GABA B are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception.r Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABA A receptors.r Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain.Abstract It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABA A or GABA B receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABA A and GABA B receptor antagonists increased the stretch response. However, while the noxious distension-induced VMR was attenuated in the presence of GABA A and GABA B receptor agonists, the VMR was only consistently increased by GABA A receptor antagonists. These results suggest Emanuel Loeza-Alcocer received his PhD in neurobiology in the laboratory of Professor Rodolfo Delgado-Lezama in Mexico City. His research was focused on characterizing the GABAergic mechanisms underlying the presynaptic inhibition of sensory neurons. At present, he investigates peripheral GABAergic inhibitory mechanisms in the colon in the group of Michael Gold PhD at University of Pittsburgh, USA. His long-term goal is to understand how peripheral GABAergic inhibition modifies sensory perception in health and disease. E. Loeza-Alcocer and others J Physiol 597.13that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling ...

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Section: Discussionmentioning

confidence: 99%

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Loeza‐Alcocer

McPherson

Gold

2019

The Journal of Physiology

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“…encode for genes involved in GABA production, suggesting a microbial participation in the production of this neurotransmitter within the gut [67,68]. Indeed, GABA-A receptors have been recently identified in the mouse colon [69,70]. Interestingly, we recently observed that rat colon expresses steroidogenic capability and, in particular, an high production of a T metabolite, such as the 3α-diol [71].…”

Section: Discussionmentioning

confidence: 96%

Alterations of gut microbiota composition in post-finasteride patients: a pilot study

Borgo

Macandog

Diviccaro

et al. 2020

J Endocrinol Invest

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Purpose Post-finasteride syndrome (PFS) has been reported in a subset of patients treated with finasteride (an inhibitor of the enzyme 5alpha-reductase) for androgenetic alopecia. These patients showed, despite the suspension of the treatment, a variety of persistent symptoms, like sexual dysfunction and cognitive and psychological disorders, including depression. A growing body of literature highlights the relevance of the gut microbiota-brain axis in human health and disease. For instance, alterations in gut microbiota composition have been reported in patients with major depressive disorder. Therefore, we have here analyzed the gut microbiota composition in PFS patients in comparison with a healthy cohort. Methods Fecal microbiota of 23 PFS patients was analyzed by 16S rRNA gene sequencing and compared with that reported in ten healthy male subjects. Results Sexual dysfunction, psychological and cognitive complaints, muscular problems, and physical alterations symptoms were reported in more than half of the PFS patients at the moment of sample collection. The quality sequence check revealed a low library depth for two fecal samples. Therefore, the gut microbiota analyses were conducted on 21 patients. The α-diversity was significantly lower in PFS group, showing a reduction of richness and diversity of gut microbiota structure. Moreover, when visualizing β-diversity, a clustering effect was found in the gut microbiota of a subset of PFS subjects, which was also characterized by a reduction in Faecalibacterium spp. and Ruminococcaceae UCG-005, while Alloprevotella and Odoribacter spp were increased compared to healthy control. Conclusion Gut microbiota population is altered in PFS patients, suggesting that it might represent a diagnostic marker and a possible therapeutic target for this syndrome.

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“…qPCR amplifications were performed to assess changes in the mRNA levels for the following inflammatory genes, using pre-designed Taqman primers/probes purchased from Life Technologies (ThermoFisher scientific): IL1β (Mm00434228_m1); TNF-α (Mm00443258_m1); IL 6 (Mm00446190_m1); CSF1 (Mm00432686_m1); CCL2 (Mm00441242_m1) and CCL3 (Mm00441259_g1), in samples from the LC and hippocampus, according to our previously published protocols (Seifi et al 2018). Gapdh (assay ID: Mm99999915_g1) gene expression was used as the housekeeping gene.…”

Section: Methodsmentioning

confidence: 99%

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

Kelly

Seifi

et al. 2020

Preprint

Self Cite

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Amyloid β oligomers (AβO) are potent modulators of two key Alzheimer's pathological processes, namely synaptic dysfunction and tau tangle formation in various brain regions. Remarkably, the impact of AβO in one of the earliest brain regions to exhibit Alzheimer's pathology, the locus coeruleus (LC), remains to be determined. Of particular importance is the effect of AβO on the excitability of individual LC neurons. This parameter determines brain-wide noradrenaline (NA) release, and thus NA-mediated brain functions, including cognition, emotion and immune function, which are all severely compromised in Alzheimer's. Using a mouse model of increased Aβ production (APP-PSEN1), together with correlative histopathological analyses in post mortem Alzheimer's patient samples, we determined the impact of Aβ pathology on various correlates of LC neuronal integrity. AβO immunoreactivity in the LC of APP-PSEN1 mice was replicated in patient samples, presenting as individual clusters located both intraneuronally, in mitochondrial compartments, as well as extracellularly in association with inhibitory synapses. No specific signal was detected in either patient control or wild type mouse samples. Accompanying this AβO expression profile was LC neuronal hyperexcitability and indicators of oxidative stress in APP-PSEN1 mice. LC hyperexcitability arose from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA-A receptor (GABA A R) α 3 subunit. Importantly, this altered LCα 3-GABA A R expression profile overlapped with AβO expression in both APP-PSEN1 mice and Alzheimer's patient samples. Finally, strychninesensitive glycine receptors (GlyRs) remained resilient to AβO-induced changes and their activation reversed LC hyperexcitability. Alongside this first demonstration of 4 AβO expression in the LC of Alzheimer's patients, the study is also first to reveal a direct association between AβO and LC neuronal excitability. GlyR-α3-GABA A R modulation of AβO-dependent LC hyperexcitability could delay the onset of cognitive and psychiatric symptoms arising from LC-NA deficits, thereby significantly diminishing the disease burden for Alzheimer's patients. particular relevance to the LC, and its early presentation of Alzheimer's pathology, is the emerging synergistic role of AβO in tau tangle formation (Pickett et al. 2019; Shin et al. 2019b). Intriguingly, while notable LC neuronal loss, attributed to tauopathy, is a core feature in Alzheimer's (Chan-Palay and Asan 1989), there appears to be discordance between the onset of such pathology, and LC neurodegeneration (Weinshenker 2018). Given such considerable evidence, it is reasonable to speculate that in the LC, initial, pre-symptomatic insults in the form of tau tangle and AβO interactions, cooperate to set in motion a range of pathological changes such as synaptic dysfunction, oxidative stress (De Felice et al. 2007) and altered LC excitability (Sanchez-Padilla et al. 2014). Such changes are likely to prove crucial in terms of the long-term viabili...

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GABAA Receptor Subtypes Regulate Stress-Induced Colon Inflammation in Mice

Cited by 42 publications

References 39 publications

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Alterations of gut microbiota composition in post-finasteride patients: a pilot study

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

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