Microglial Displacement of GABAergic Synapses Is a Protective Event during Complex Febrile Seizures

Wan, Yong; Feng, Bo; You, Yi; Yu, Jie; Xu, Cenglin; Dai, Haibin; Trapp, Bruce D.; Shi, Peng; Chen, Zhong; Hu, Weiwei

doi:10.1016/j.celrep.2020.108346

Cited by 44 publications

(46 citation statements)

References 84 publications

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“…In the current study, we discovered T. gondii infection triggers microglia to specifically ensheath excitatory pyramidal neurons in neocortex and that GABAergic perisomatic synapse loss occurs on these excitatory cells. These findings are in line with other models of epilepsy that show preferential ensheathment of excitatory cortical neurons and subsequent displacement of GABAergic perisomatic synapses from these cells (Wan et al, 2020). Microglia, however, are not the only ones that preferentially interact with excitatory neurons.…”

Section: Discussionsupporting

confidence: 91%

“…At the initial stages of the infection, T. gondii infection follows a similar pattern of widespread microglial activation and increase in phagocytic cells (here, likely attributed to both microglial proliferation and monocyte recruitment from the periphery), as is commonly seen in other, but not all, types of neuroinflammation or neurodegeneration (Borges et al, 2003, Feng et al, 2019, Hagan et al, 2020). Moreover, T. gondii infection induces microglia to extensively ensheath the somata of neurons, a process first described in the peripheral central nervous system following injury to the facial nerve (Blinzinger and Kreutzberg, 1968, Shibasaki et al, 2007, Chen et al, 2014, Wan et al, 2020). Interestingly, ensheathment of neurons in models of induced epilepsy has been described as a transient process, whereby microglia temporarily displace perisomatic synapses as a response to aberrant GABAergic signaling from presynaptic nerve terminals, thus serving as a protective mechanism to the neuron (Wan et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, T. gondii infection induces microglia to extensively ensheath the somata of neurons, a process first described in the peripheral central nervous system following injury to the facial nerve (Blinzinger and Kreutzberg, 1968, Shibasaki et al, 2007, Chen et al, 2014, Wan et al, 2020). Interestingly, ensheathment of neurons in models of induced epilepsy has been described as a transient process, whereby microglia temporarily displace perisomatic synapses as a response to aberrant GABAergic signaling from presynaptic nerve terminals, thus serving as a protective mechanism to the neuron (Wan et al, 2020). Furthermore, displacement of GABAergic perisomatic synapses results in an increase in synchronized neuronal activity which triggers neuronal expression of anti-apoptotic and neurotrophic molecules as neuroprotection (Chen et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Complement-dependent loss of inhibitory synapses on pyramidal neurons followingToxoplasma gondiiinfection

Carrillo

Crawley

et al. 2022

Preprint

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The apicomplexan parasite Toxoplasma gondii has developed mechanisms to establish a central nervous system infection in virtually all warm-blooded animals. Acute T. gondii infection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, non-human primates, and rodents have linked chronic T. gondii infection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. We previously demonstrated that T. gondii infection triggers the loss of perisomatic inhibitory synapses, an important source of inhibition on excitatory pyramidal cells, and a type of synapse that is disrupted in neurological and neuropsychiatric disorders. Similar to other instances of inflammation and neurodegeneration, we showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. However, in the case of T. gondii-induced synapse loss, phagocytic cells target and ensheath the cell bodies of telencephalic neurons. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons. In contrast, inhibitory cortical interneuron subtypes are not extensively ensheathed by phagocytic cells following infection. Moreover, we show that infection induces expression of complement C3 protein by these excitatory neurons and that C3 is required for the loss of perisomatic inhibitory synapses, albeit not through activation of the classical complement pathway. Together, these findings provide evidence that T. gondii infection induces changes in excitatory pyramidal neurons that trigger selective removal of inhibitory perisomatic synapses in the infected neocortex and provide a novel role for complement in remodeling of inhibitory circuits in the infected brain.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Complement-dependent loss of inhibitory synapses on pyramidal neurons followingToxoplasma gondiiinfection

Carrillo

Crawley

et al. 2022

Preprint

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“…Mice lacking the P2Y12 receptor display reduced microglia–neuron interactions alongside more severe seizures and lethality during status epilepticus (Badimon et al, 2020; Eyo et al, 2014). During febrile seizures, microglia can also displace GABAergic synapses through a P2Y12‐dependent mechanism, resulting in reduced seizure intensity (Wan et al, 2020). Thus, microglial recruitment can dampen neuronal hyperactivity, limiting acute seizure severity in the process.…”

Section: Microglia Sense and Regulate Neuronal Hyperactivitymentioning

confidence: 99%

How microglia sense and regulate neuronal activity

Umpierre

2020

Glia

115

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Microglia are innate immune cells of the central nervous system that sense extracellular cues. Brain injuries, inflammation, and pathology evoke dynamic structural responses in microglia, altering their morphology and motility. The dynamic motility of microglia is hypothesized to be a critical first step in sensing local alterations and engaging in pattern‐specific responses. Alongside their pathological responses, microglia also sense and regulate neuronal activity. In this review, we consider the extracellular molecules, receptors, and mechanisms that allow microglia to sense neuronal activity changes under both hypoactivity and hyperactivity. We also highlight emerging in vivo evidence that microglia regulate neuronal activity, ranging from physiological to pathophysiological conditions. In addition, we discuss the emerging role of calcium signaling in microglial responses to the extracellular environment. The dynamic function of microglia in monitoring and influencing neuronal activity may be critical for brain homeostasis and circuit modification in health and disease.

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“…Wan et al set out to understand mechanisms for how complex FS result in epileptogenesis in their study. 2 They were especially interested in a role for microglia as microglia are innate immune cells associated with inflammation, microglia are activated following complex FS, 3 and inflammation is involved in the development of FS. 4 They employed a powerful combination of molecular tools, electrophysiology, and transgenic animals.…”

Section: Commentarymentioning

confidence: 99%