NMDA receptor inhibition increases, synchronizes, and stabilizes the collective pancreatic beta cell activity: Insights through multilayer network analysis

Author summary Information processing in tissues is regulated by networks of interacting cells and through crosstalk with their environment. This is also true for islets of Langerhans in which several hundreds of beta cells are interconnected to ensure a proper secretion of insulin, a hormone crucial for the control of metabolic homeostasis. Since the loss of coordinated cellular activity is accompanied by a disruption of insulin secretion patterns, one of the main hallmarks of diabetes, it is of utmost importance to understand the underlying mechanisms that drive collective cellular activity in the islets and how these are affected in disease. Recently, NMDA receptor inhibitors were shown to boost beta cell activity and insulin secretion and were therefore suggested as a potential antidiabetic drugs. However, their impact on the multicellular dynamics is not known. In the present study, we address this issue by combining high-frequency functional multicellular calcium imaging in pancreas tissue slices with network science approaches. Our findings reveal that NMDA receptor inhibition increases and synchronizes the activity of beta cell populations. Moreover, by considering individual intercellular calcium waves as network layers we show that NMDA receptor inhibition stabilizes the course of intercellular signals and confines the wave initiator regions. NMDA receptors promote repolarization in pancreatic beta cells and thereby reduce glucose-stimulated insulin secretion. Therefore, NMDA receptors are a potential therapeutic target for diabetes. While the mechanism of NMDA receptor inhibition in beta cells is rather well understood at the molecular level, its possible effects on the collective cellular activity have not been addressed to date, even though proper insulin secretion patterns result from well-synchronized beta cell behavior. The latter is enabled by strong intercellular connectivity, which governs propagating calcium waves across the islets and makes the heterogeneous beta cell population work in synchrony. Since a disrupted collective activity is an important and possibly early contributor to impaired insulin secretion and glucose intolerance, it is of utmost importance to understand possible effects of NMDA receptor inhibition on beta cell functional connectivity. To address this issue, we combined confocal functional multicellular calcium imaging in mouse tissue slices with network science approaches. Our results revealed that NMDA receptor inhibition increases, synchronizes, and stabilizes beta cell activity without affecting the velocity or size of calcium waves. To explore intercellular interactions more precisely, we made use of the multilayer network formalism by regarding each calcium wave as an individual network layer, with weighted directed connections portraying the intercellular propagation. NMDA receptor inhibition stabilized both the role of wave initiators and the course of waves. The findings obtained with the experimental antagonist of NMDA receptors, MK-801, were additionally validated with dextrorphan, the active metabolite of the approved drug dextromethorphan, as well as with experiments on NMDA receptor KO mice. In sum, our results provide additional and new evidence for a possible role of NMDA receptor inhibition in treatment of type 2 diabetes and introduce the multilayer network paradigm as a general strategy to examine effects of drugs on connectivity in multicellular systems.

Automated summary

Our study demonstrates that NMDA receptor inhibition enhances and synchronizes beta cell activity, as well as stabilizes intercellular calcium wave propagation within the islets of Langerhans. This finding highlights the potential of NMDA receptors as a therapeutic target for diabetes and introduces the multilayer network paradigm as a useful strategy to investigate drug effects on connectivity in multicellular systems.