Probes for INS

Diabetes leads to intestinal barrier dysfunction. 5-Hydroxytryptamine receptor 4 (5-HT4R) is distributed in the colonic mucosa, but little is known about the role of 5-HT4R activation in diabetes-evoked colonic barrier dysfunction. This study investigates whether activation of 5-HT4Rs on goblet cells (GCs) protects the colon from commensal bacterial translocation in diabetic mice. Expression of 5-HT4R detected inside the colonic epithelium by RNAscope in situ hybridization was further observed within the mucin 2 (MUC2)-immunoreactive GCs. In diabetic mice, neither 5-HT4R transcription nor protein levels were altered compared with those in nondiabetic mice. Bacterial translocation was characterized by 16S rRNA RNAscope in situ hybridization and manifested in both crypts and lamina propria of the colon in diabetic mice. Moreover, mucin production and MUC2 expression were significantly decreased in diabetic mice. Furthermore, the loss of mitochondrial cristae of GCs and the down-regulation of mitofilin, the core protein maintaining mitochondrial homeostasis, were observed in diabetic mice. However, long-term treatment with 5-HT4R agonist in diabetic mice not only prevented bacterial penetration of the whole colonic mucosa but also promoted mucin production and MUC2 expression. Markedly, 5-HT4R agonist also restored the mitochondrial cristae of GCs and up-regulated mitofilin. However, co-administration of 5-HT4R antagonist abolished the effects of 5-HT4R agonist on diabetic mice. These findings indicate that 5-HT4R in colonic mucosa is an effective target for the treatment of diabetes-induced colonic mucous barrier dysfunction.

Hyperactivity of pyramidal neurons (PNs) in CA1 is an early event in Alzheimer’s disease (AD). However, factors accounting for the hyperactivity of CA1 PNs remain to be completely investigated. In the present study, we found that the serotonergic signaling was abnormal in the hippocampus of hAPP-J20 mice. Interestingly, chemogenetic activation of serotonin (5-hydroxytryptamine, 5-HT) neurons in the median raphe nucleus (MRN) attenuated the activity of CA1 PNs in hAPP-J20 mice by regulating the intrinsic properties or inhibitory synaptic transmission of CA1 PNs through 5-HT3aR and/or 5-HT1aR. Furthermore, activating MRN 5-HT neurons improved memory in hAPP-J20 mice and this effect was mediated by 5-HT3aR and 5-HT1aR. Direct activation of 5-HT3aR and 5-HT1aR with their selective agonists also improved memory of hAPP-J20 mice. Together, we identified the impaired 5-HT/5-HT3aR and/or 5-HT/5-HT1aR signaling as new pathways contributing to the hyperexcitability of CA1 PNs and the impaired cognition in hAPP-J20 mice.