Distinct cellular mediators drive the Janus Faces of Toll-like Receptor 4 regulation of network excitability which impacts working memory performance after brain Injury

Korgaonkar, Akshata A.; Liu, Ying; Guevarra, Jenieve; Pang, Kevin; Santhakumar, Vijayalakshmi; Nguyen, Susan

doi:10.1101/750869

Cited by 3 publications

(3 citation statements)

References 73 publications

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“…In addition, excitability of the cerebral dentate gyrus after brain injury accompanied by increased TLR4 signaling is mediated by the synaptic AMPAR current, while the NMDAR, another glutamate receptor, does not change [18]. Consistent with this, blocking of TLR4 signaling after brain injury can reduce the calcium-permeable AMPAR current of granular cells in the dentate gyrus, reduce neural network excitability and epilepsy susceptibility [19,20]. Based on the above studies, we speculate that AR-induced OD may be accompanied with AMPAR-mediated neuronal damage induced by microglia activation, and dopamine D2 receptor agonists are expected to reverse this process.…”

Section: Introductionmentioning

confidence: 70%

Activation of Dopamine D2 Receptor Alleviates Neuroinflammation and Neuronal Injury in Mice Model of Allergic Rhinitis With Olfactory Dysfunction

Liu

Qin

et al. 2020

Preprint

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Background: Allergic rhinitis (AR) is a common chronic allergic disease of the upper airway that not only causes peripheral inflammation, but also induces neuroinflammation in the hippocampus, prefrontal cortex, olfactory bulb and other brain areas. Recent studies have suggested that the dopamine D2 receptor acts as a key target in regulating immune functions and neuroinflammatory reaction, which may be a promising target for AR-induced olfactory dysfunction (OD).Methods: An AR mouse model with OD induced by ovalbumin (OVA) were constructed. A coculture system of olfactory bulb neurons (OBNs) and microglias was established. The buried food pellet test was to evaluate the olfactory function of the mice. Immunofluorescence staining, HE staining, ELISA, Western blotting, and TUNEL staining were also used to investigate the molecular mechanisms underlying the anti-inflammatory effects of the dopamine D2 receptor in AR-induced OD.Results: We confirmed that AR mice with or without OD had the characteristics of AR, but the expression of the microglial marker CD11b and the related cytokines (TNF-α, IL-1β and IL-6) in the AR mice with OD were significantly increased in the olfactory bulb compared with those of mice without OD. Nasal administration of quinpirole, a dopamine D2 receptor agonist, shortened the time to find the food pellets, inhibited the expression of TLR4/MyD88/NF-κB signalings and the levels of TNF-α, IL-1β and IL-6. In the coculture system of OBNs and microglias, quinpirole inhibited the release of TLR4/MyD88/NF-κB signalings-dependent inflammatory cytokines in the microglias, which was accompanied by decreased AMPA receptor GluR1, increased GluR2 and reduced TUNEL positive cells in the OBNs.Conclusion: Activation of the dopamine D2 receptor inhibits the release of inflammatory cytokines through the microglia-dependent TLR4/MyD88/NF-κB signalings, alleviates AMPA receptor-mediated damage of the olfactory bulb, and protects olfactory function.

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Section: Introductionmentioning

confidence: 70%

Activation of Dopamine D2 Receptor Alleviates Neuroinflammation and Neuronal Injury in Mice Model of Allergic Rhinitis With Olfactory Dysfunction

Liu

Qin

et al. 2020

Preprint

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“…In the rat DG, neuronal TLR4 increased after fluid percussion injury, while electrophysiological records showed that TLR4 activation enhanced dentate network excitability in injured rats (Korgaonkar et al, 2020a; Li et al, 2015). As AMPA currents in neuronal cultures depleted of glia were enhanced by agonists of TLR4 and reduced by TLR4 antagonists, it was believed that neuronal TLR4 signaling enhances excitability in the injured brain (Korgaonkar et al, 2020b). These experiments suggest that neuronal TLR4 modulates dentate excitability.…”

Section: Discussionmentioning

confidence: 99%

“…As the authors mention, it could be due to differential recruitment of glial versus neuronal signaling. Globally, neuronal TLR4 signaling is predominant in pathological situation, at least in adult rats, underlying an increased excitability in the DG (Korgaonkar et al, 2020b). However, these studies concerned early posttraumatic injury events and reveal modulation of neuronal excitability by TLR4 signaling in the DG only, while our present observation concerned the CA1 area.…”

Section: Discussionmentioning

confidence: 99%

Astrogliosis and compensatory neurogenesis after the first ethanol binge drinking‐like exposure in the adolescent rat

Vilpoux

Fouquet

Deschamps

et al. 2021

Alcoholism Clin & Exp Res

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Background Multiple ethanol binge drinking‐like exposures during adolescence in the rat induce neuroinflammation, loss of neurogenesis, and cognitive deficits in adulthood. Interestingly, the first ethanol binge drinking‐like exposure during adolescence also induces short‐ term impairments in cognition and synaptic plasticity in the hippocampus though the cellular mechanisms of these effects are unclear. Here, we sought to determine which of the cellular effects of ethanol might play a role in the disturbances in cognition and synaptic plasticity observed in the adolescent male rat after two binge‐like ethanol exposures. Methods Using immunochemistry, we measured neurogenesis, neuronal loss, astrogliosis, neuroinflammation, and synaptogenesis in the hippocampus of adolescent rats 48 h after two binge‐like ethanol exposures (3 g/kg, i.p., 9 h apart). We used flow cytometry to analyze activated microglia and identify the TLR4‐expressing cell types. Results We detected increased hippocampal doublecortin immunoreactivity in the subgranular zone (SGZ) of the dentate gyrus (DG), astrogliosis in the SGZ, and a reduced number of mature neurons in the DG and in CA3, suggesting compensatory neurogenesis. Synaptic density decreased in the stratum oriens of CA1 revealing structural plasticity. There was no change in microglial TLR4 expression or in the number of activated microglia, suggesting a lack of neuroinflammatory processes, although neuronal TLR4 was decreased in CA1 and DG. Conclusions Our findings demonstrate that the cognitive deficits associated with hippocampal synaptic plasticity alterations that we previously characterized 48 h after the first binge‐like ethanol exposures are associated with hippocampal structural plasticity, astrogliosis, and decreased neuronal TLR4 expression, but not with microglia reactivity.

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Early Deficits in Dentate Circuit and Behavioral Pattern Separation after Concussive Brain Injury

Corrubia

Huang

Nguyen

et al. 2023

Preprint

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Traumatic brain injury leads to cellular and circuit changes in the dentate gyrus, a gateway to hippocampal information processing. Cell intrinsic sparse granule cell firing and strong feedback inhibition in the dentate are proposed as critical to its ability to generate unique representation of similar inputs by a process known as pattern separation. Here we evaluate the impact of brain injury on cellular decorrelation of temporally patterned inputs in slices and behavioral discrimination of spatial locations in vivo one week after concussive lateral fluid percussion injury (FPI) in mice. Despite posttraumatic increases in perforant path evoked excitatory drive to granule cells and enhanced ΔFosB labeling, indicating sustained increase in excitability, the reliability of granule cell spiking was not compromised after FPI. Although granule cells continued to effectively decorrelate output spike trains recorded in response to similar temporally patterned input sets after FPI, their ability to decorrelate highly similar input patterns was reduced. In parallel, encoding of similar spatial locations in a novel object location task that involves the dentate inhibitory circuits was impaired one week after FPI. Injury induced changes in pattern separation were accompanied by loss of somatostatin expressing inhibitory neurons in the hilus. Together, these data suggest that the early posttraumatic changes in the dentate circuit undermine dentate circuit decorrelation of temporal input patterns as well as behavioral discrimination of similar spatial locations, both of which could contribute to deficits in episodic memory.

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Distinct cellular mediators drive the Janus Faces of Toll-like Receptor 4 regulation of network excitability which impacts working memory performance after brain Injury

Cited by 3 publications

References 73 publications

Activation of Dopamine D2 Receptor Alleviates Neuroinflammation and Neuronal Injury in Mice Model of Allergic Rhinitis With Olfactory Dysfunction

Activation of Dopamine D2 Receptor Alleviates Neuroinflammation and Neuronal Injury in Mice Model of Allergic Rhinitis With Olfactory Dysfunction

Astrogliosis and compensatory neurogenesis after the first ethanol binge drinking‐like exposure in the adolescent rat

Early Deficits in Dentate Circuit and Behavioral Pattern Separation after Concussive Brain Injury

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