Microglial Gi-dependent dynamics regulate brain network hyperexcitability

Merlini, Mario; Rafalski, Victoria A.; Ma, Keran; Kim, Keun‐Young; Bushong, Eric A.; Coronado, Pamela E. Rios; Yan, Zhaoqi; Mendiola, Andrew S.; Sözmen, Elif G.; Ryu, Jae K.; Haberl, Matthias G.; Madany, Matthew; Sampson, Daniel Naranjo; Petersen, Mark A.; Bardehle, Sophia; Tognatta, Reshmi; Dean, Terry; Acevedo, Rosa Meza; Cabriga, Belinda; Thomas, Reuben; Coughlin, Shaun R.; Ellisman, Mark H.; Palop, Jorge J.; Akassoglou, Katerina

doi:10.1038/s41593-020-00756-7

Cited by 101 publications

(89 citation statements)

References 44 publications

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“…This finding underscores that microglia may retain activation features, possibly contributing to network excitability, even in the absence of cell proliferation. In this respect, activated microglia involvement in seizures was recently related to cellular process mobility and contacts onto neuronal somata 20 …”

Section: Discussionmentioning

confidence: 99%

Microglia proliferation plays distinct roles in acquired epilepsy depending on disease stages

et al. 2021

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Objective Microgliosis occurs in animal models of acquired epilepsy and in patients. It includes cell proliferation that is associated with seizure frequency and decreased neuronal cells in human epilepsy. The role of microglia proliferation in the development of acquired epilepsy is unknown; thus, we examined its contribution to spontaneous seizure, neurodegeneration, and cognitive deficits in different disease phases. Methods We used a model of acquired epilepsy triggered by intra‐amygdala kainic acid in C57BL6N adult male mice. Mice were electroencephalographically (EEG) monitored (24/7) during status epilepticus and in early and chronic disease. Microglia proliferation was blocked by GW2580, a selective CSF1 receptor inhibitor, supplemented in the diet for 21 days from status epilepticus onset. Then, mice were returned to placebo diet until experiment completion. Control mice were exposed to status epilepticus and fed with placebo diet. Experimental mice were tested in the novel object recognition test (NORT) and in Barnes maze, and compared to control and sham mice. At the end of the behavioral test, mice were killed for brain histopathological analysis. Additionally, seizure baseline was monitored in chronic epileptic mice, then mice were fed for 14 days with GW2580 or placebo diet under 24/7 EEG recording. Results GW2580 prevented microglia proliferation in mice undergoing epilepsy, whereas it did not affect microglia or basal excitatory neurotransmission in the hippocampus of naive mice. Mice with occluded microglia proliferation during early disease development underwent status epilepticus and subsequent epilepsy similar to placebo diet mice, and were similarly impaired in NORT, with improvement in Barnes maze. GW2580‐treated mice displayed neuroprotection in the hippocampus. In contrast, blockade of microglia proliferation in chronic epileptic mice resulted in spontaneous seizure reduction versus placebo mice. Significance Microglia proliferation during early disease contributes to neurodegeneration, whereas in late chronic disease it contributes to seizures. Timely pharmacological interference with microglia proliferation may offer a potential target for improving disease outcomes.

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Section: Discussionmentioning

confidence: 99%

Microglia proliferation plays distinct roles in acquired epilepsy depending on disease stages

et al. 2021

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“…Thus, microglia could use autocrine ATP signaling to self-propagate the motility of their processes via binding to P2Y12 while other signals indicate specific synaptic targets. Depending on the method of intercellular signaling, purines could serve several functions in the process of synaptic modulation, including allowing microglia to sense neuronal activity [39,40], recruiting microglial processes to synaptic elements either alone [14,18,39] or in combination with the go and stop signals that allow synaptic specificity [5,54], mediating the pruning of synapses by microglia [5,14], or recruiting microglial pathways that in turn alter neuronal activity [55,56]. An important aspect in determining cell-cell interactions and the precise function of purinergic signaling in the process of synaptic modulation will be to identify the source of the purines that activate the P2Y12 receptor on microglia.…”

Section: Purinergic Signaling and Synaptic Plasticitymentioning

confidence: 99%

Loss of P2Y12 Has Behavioral Effects in the Adult Mouse

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et al. 2021

IJMS

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While microglia have been established as critical mediators of synaptic plasticity, the molecular signals underlying this process are still being uncovered. Increasing evidence suggests that microglia utilize these signals in a temporally and regionally heterogeneous manner. Subsequently, it is necessary to understand the conditions under which different molecular signals are employed by microglia to mediate the physiological process of synaptic remodeling in development and adulthood. While the microglial purinergic receptor P2Y12 is required for ocular dominance plasticity, an adolescent form of experience-dependent plasticity, it remains unknown whether P2Y12 functions in other forms of plasticity at different developmental time points or in different brain regions. Using a combination of ex vivo characterization and behavioral testing, we examined how the loss of P2Y12 affects developmental processes and behavioral performance in adulthood in mice. We found P2Y12 was not required for an early form of plasticity in the developing visual thalamus and did not affect microglial migration into barrels in the developing somatosensory cortex. In adult mice, however, the loss of P2Y12 resulted in alterations in recognition and social memory, as well as anxiety-like behaviors, suggesting that while P2Y12 is not a universal regulator of synaptic plasticity, the loss of P2Y12 is sufficient to cause functional defects.

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“…Microglial cells are physiological guardians and modulators of neuronal activity, which can protect brain tissue from excessive neuronal firing. This fundamental function is mostly achieved by the ability of microglia to sense ADP, generated by the rapid breakdown of neuronal ATP released as cotransmitter, through membrane P2Y 12 receptors which in turn control microglia chemotaxis and process dynamics (Badimon et al, 2020) and triggers a cascade of inhibitory events on neurons (Merlini et al, 2021). However, under chronic inflammatory conditions, in the presence of nerve injury or in chronic migraine, microglia become overactivated and shift toward a detrimental state, which involves overexpressed P2Y 12 receptors (Jing et al, 2019;Yu et al, 2019).…”

Section: Purinergic Agents Targeting Glial Cells To Treat Pain: What mentioning

confidence: 99%