Microglia contribute to neuronal synchrony despite endogenous ATP-related phenotypic transformation in acute mouse brain slices

Péter Berki, Csaba Cserép, Zsuzsanna Környei, Balázs Pósfai, Eszter Szabadits, Andor Domonkos, Anna Kellermayer, Miklós Nyerges, Xiaofei Wei, Istvan Mody, Araki Kunihiko, Heinz Beck, He Kaikai, Wang Ya, Nikolett Lénárt, Zhaofa Wu, Miao Jing, Yulong Li, Attila I. Gulyás and Ádám Dénes ()
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Péter Berki: Semmelweis University
Csaba Cserép: HUN-REN Institute of Experimental Medicine
Zsuzsanna Környei: HUN-REN Institute of Experimental Medicine
Balázs Pósfai: HUN-REN Institute of Experimental Medicine
Eszter Szabadits: HUN-REN Institute of Experimental Medicine
Andor Domonkos: HUN-REN Institute of Experimental Medicine
Anna Kellermayer: HUN-REN Institute of Experimental Medicine
Miklós Nyerges: HUN-REN Institute of Experimental Medicine
Xiaofei Wei: The David Geffen School of Medicine at UCLA
Istvan Mody: The David Geffen School of Medicine at UCLA
Araki Kunihiko: Medical University of Bonn
Heinz Beck: Medical University of Bonn
He Kaikai: Peking University
Wang Ya: Chinese Institute for Brain Research
Nikolett Lénárt: HUN-REN Institute of Experimental Medicine
Zhaofa Wu: Chinese Academy of Sciences
Miao Jing: Chinese Institute for Brain Research
Yulong Li: Peking University
Attila I. Gulyás: HUN-REN Institute of Experimental Medicine
Ádám Dénes: HUN-REN Institute of Experimental Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: Abstract Acute brain slices represent a workhorse model for studying the central nervous system (CNS) from nanoscale events to complex circuits. While slice preparation inherently involves tissue damage, it is unclear how microglia, the main immune cells and damage sensors of the CNS react to this injury and shape neuronal activity ex vivo. To this end, we investigated microglial phenotypes and contribution to network organization and functioning in acute brain slices. We reveal time-dependent microglial phenotype changes influenced by complex extracellular ATP dynamics through P2Y12R and CX3CR1 signalling, which is sustained for hours in ex vivo mouse brain slices. Downregulation of P2Y12R and changes of microglia-neuron interactions occur in line with alterations in the number of excitatory and inhibitory synapses over time. Importantly, functional microglia modulate synapse sprouting, while microglial dysfunction results in markedly impaired ripple activity both ex vivo and in vivo. Collectively, our data suggest that microglia are modulators of complex neuronal networks with important roles to maintain neuronal network integrity and activity. We suggest that slice preparation can be used to model time-dependent changes of microglia-neuron interactions to reveal how microglia shape neuronal circuits in physiological and pathological conditions.

Date: 2024
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DOI: 10.1038/s41467-024-49773-1

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