Asymmetric activation of microglia in the hippocampus drives anxiodepressive consequences of trigeminal neuralgia in rodents.

BACKGROUND AND PURPOSE: Patients suffering from trigeminal neuralgia are often accompanied by anxiety and depression. Microglia-mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in trigeminal neuralgia-induced anxiodepression remains unclear. EXPERIMENTAL APPROACH: Unilateral constriction of the infraorbital nerve (CION) was performed to establish trigeminal neuralgia in rat and mouse models. Mechanical allodynia and anxiodepressive-like behaviours were measured. Optogenetic and pharmacological manipulations were employed to investigate the role of hippocampal microglia in anxiety and depression caused by trigeminal neuralgia. KEY RESULTS: Trigeminal neuralgia activated ipsilateral but not contralateral hippocampal microglia, up-regulated ipsilateral hippocampal ATP and interleukin-1ß (IL-1ß) levels, impaired ipsilateral hippocampal long-term potentiation (LTP) and induced anxiodepressive-like behaviours in a time-dependent manner in rodents. Pharmacological or optogenetic inhibition of ipsilateral hippocampal microglia completely blocked trigeminal neuralgia-induced anxiodepressive-like behaviours. Activation of unilateral hippocampal microglia directly elicited an anxiodepressive state and impaired hippocampal LTP. Knockdown of ipsilateral hippocampal P2X7 receptors prevented trigeminal neuralgia-induced microglial activation and anxiodepressive-like behaviours. Furthermore, we demonstrated that microglia-derived IL-1ß mediated microglial activation-induced anxiodepressive-like behaviours and LTP impairment. CONCLUSION AND IMPLICATIONS: These findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviours via IL-1ß. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia-induced anxiety and depression was uncovered. The approaches targeting microglia and P2X7 signalling might offer novel therapies for trigeminal neuralgia-related anxiety and depressive disorder.

Regulating the Golgi apparatus sorting of proteinase A to decrease its excretion in Saccharomyces cerevisiae.

Beer foam stability, a key factor in evaluating overall beer quality, is influenced by proteinase A (PrA). Actin-severing protein cofilin and Golgi apparatus-localized Ca2+ ATPase Pmr1 are involved in protein sorting at the trans-Golgi network (TGN) in yeast Curwin et al. (Mol Biol Cell 23:2327-2338, 2012). To reduce PrA excretion into the beer fermentation broth, we regulated the Golgi apparatus sorting of PrA, thereby facilitating the delivery of more PrA to the vacuoles in the yeast cells. In the present study, the cofilin-coding gene COF1 and the Pmr1-coding gene PMR1 were overexpressed in the parental strain W303-1A and designated as W + COF1 and W + PMR1, respectively. The relative expression levels of COF1 in W + COF1 and PMR1 in W + PMR1 were 5.26- and 19.76-fold higher than those in the parental strain. After increases in the expression levels of cofilin and Pmr1 were confirmed, the PrA activities in the wort broth fermented with W + COF1, W + PMR1, and W303-1A were measured. Results showed that the extracellular PrA activities of W + COF1 and W + PMR1 were decreased by 9.24% and 13.83%, respectively, at the end of the main fermentation compared with that of W303-1A. Meanwhile, no apparent differences were found on the fermentation performance of recombinant and parental strains. The research uncovers an effective strategy for decreasing PrA excretion in Saccharomyces cerevisiae.