Systemic LPS-induced microglial activation results in increased GABAergic tone: A mechanism of protection against neuroinflammation in the medial prefrontal cortex in mice

Jiang, Jinxiang; Tang, Binliang; Wang, Lei; Huo, Qingwei; Tan, Shanzhong; Misrani, Afzal; Han, Yuanyuan; Li, Huidong; Hu, Hai-Dong; Wang, Jichen; Cheng, Tinghui; Tabassum, Sidra; Chen, Ming; Xie, Wenyuan; Long, Cheng; Yang, Li

doi:10.1016/j.bbi.2021.09.017

Cited by 43 publications

(27 citation statements)

References 123 publications

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“…Indeed, it was shown that Baclofen administration to microglia cell cultures leads to a decrease of inflammatory mediators such as P38 MAP Kinases [27]. Moreover, the GABAergic system was recently described as a key target to modulate neuroinflammation [28]. The mechanisms behind our observations are not fully understood, and further studies must be performed to understand it.…”

Section: Discussionmentioning

confidence: 84%

Acute baclofen administration promotes functional recovery after spinal cord injury

Sousa

Pinho²,

Monteiro³

et al. 2023

The Spine Journal

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Section: Discussionmentioning

confidence: 84%

Acute baclofen administration promotes functional recovery after spinal cord injury

Sousa

Pinho²,

Monteiro³

et al. 2023

The Spine Journal

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“…Based on these results, increased expression and activity of KCC2 provide the explanation for the enhanced GABAergic synaptic inhibition and memory deficits of adult LPS mice. A recent study has found that there are both pre- and post-synaptic potentiations of GABAergic transmission in the prefrontal cortex accompanied with increased expressions of multiple GABAergic synapse-associated proteins 2 h after LPS challenge [ 72 ]. The study combined with our research suggests that there is difference in acute and long-term effects of inflammation on GABAergic synaptic transmission, which may be related to the involvement of different molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice

Jiang

Yang

Min

et al. 2023

J Neuroinflammation

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The mechanisms by which neonatal inflammation leads to cognitive deficits in adulthood remain poorly understood. Inhibitory GABAergic synaptic transmission plays a vital role in controlling learning, memory and synaptic plasticity. Since early-life inflammation has been reported to adversely affect the GABAergic synaptic transmission, the aim of this study was to investigate whether and how neonatal inflammation affects GABAergic synaptic transmission resulting in cognitive impairment. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days 3–5. It was found that blocking GABAergic synaptic transmission reversed the deficit in hippocampus-dependent memory or the induction failure of long-term potentiation in the dorsal CA1 in adult LPS mice. An increase of mIPSCs amplitude was further detected in adult LPS mice indicative of postsynaptic potentiation of GABAergic transmission. Additionally, neonatal LPS resulted in the increased expression and function of K+–Cl−-cotransporter 2 (KCC2) and the decreased expression of transforming growth factor-beta 1 (TGF-β1) in the dorsal CA1 during adulthood. The local TGF-β1 overexpression improved KCC2 expression and function, synaptic plasticity and memory of adult LPS mice. Adult LPS mice show hypermethylation of TGFb1 promoter and negatively correlate with reduced TGF-β1 transcripts. 5-Aza-deoxycytidine restored the changes in TGFb1 promoter methylation and TGF-β1 expression. Altogether, the results suggest that hypermethylation-induced reduction of TGF-β1 leads to enhanced GABAergic synaptic inhibition through increased KCC2 expression, which is a underlying mechanism of neonatal inflammation-induced hippocampus-dependent memory impairment in adult mice.

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“…We demonstrated here that pretreatment with C21 lessened microglial NOX2 expression and resulted in ROS production in the prefrontal cortex and hippocampus in mice subjected to LPS/MV. In addition to NOX2-derived ROS, it cannot be neglected that microglia produce a wide spectrum of neural active substances to participate in the neuroinflammatory cascade and synaptic dysfunction, such as IL-1 and TNF as well as neuroprotective factors, including BDNF which is critically involved in synaptic maturation and plasticity (Jiang et al 2022 ). Although others and our data revealed that the substantial increase in IL-1, TNF, and BDNF levels occurs concomitantly with reactive microglia, there is a limitation that we did not deeply investigate whether and how the alteration of these substances drives the subsequent neurological dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin Type 2 Receptor Pharmacological Agonist Relieves Neurocognitive Deficits via Reducing Neuroinflammation and Microglial Engulfment of Dendritic Spines

Shen

Chen

Lou

et al. 2022

J Neuroimmune Pharmacol

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Mechanically ventilated patients suffering critical illness are at high risk of developing neurocognitive impairments. Angiotensin type 2 receptor (AGTR2) has been demonstrated to be anti-inflammatory and neuroprotective. The present study thus aimed to investigate whether AGTR2 can alleviate cerebral dysfunction in mice subjected to cochallenge with lipopolysaccharide (LPS) and mechanical ventilation (MV), and to reveal the underlying mechanism. We utilized a mice model that received a single injection of LPS (1 mg/kg, intraperitoneally) followed 2 h later by MV (10 ml/kg, lasting for 2 h). Pretreatment with the AGTR2 pharmacological agonist C21 (0.03, 0.3, and 3 mg/kg, intraperitoneally, once daily, lasting for 10 days). Locomotor activity and behavioral deficits were evaluated 24 h post-MV by open-field and fear-condition tests. Brain hippocampus and prefrontal cortex tissues were collected for immunofluorescence staining and western blotting to evaluate the resulting impacts on microglia, including morphological traits, functional markers, synaptic engulfment, superoxide production, and signaling molecules. Compared with vehicle-control, pre-administrated C21 reduced the branch endpoints and length of microglia processes in a dose-dependent manner in mice subjected to LPS/MV. The neuroprotective effect of AGTR2 was behaviorally confirmed by the improvement of memory decline in LPS/MV-treated mice following C21 pretreatment. In addition to morphological alterations, C21 reduced microglial functional markers and reduced microglial-dendrite contact and microglial engulfment of synaptic protein markers. In terms of the underlying molecular mechanism, AGTR2 stimulation by C21 leads to activation of protein phosphatase 2A, which subsequently mitigates microglial PKCδ and NF-κB activation, and inhibites NOX2-derived ROS production. The AGTR2 agonist C21 alleviates behavioral deficits in those mice subjected to LPS/MV, via mechanisms that involve reactive microglia and abnormal synaptic plasticity in NOX2-derived ROS and the PKCδ-NFκB pathway. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11481-022-10054-7.

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Systemic LPS-induced microglial activation results in increased GABAergic tone: A mechanism of protection against neuroinflammation in the medial prefrontal cortex in mice

Cited by 43 publications

References 123 publications

Acute baclofen administration promotes functional recovery after spinal cord injury

Acute baclofen administration promotes functional recovery after spinal cord injury

Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice

Angiotensin Type 2 Receptor Pharmacological Agonist Relieves Neurocognitive Deficits via Reducing Neuroinflammation and Microglial Engulfment of Dendritic Spines

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