Upregulation of TRPC5 in hippocampal excitatory synapses improves memory impairment associated with neuroinflammation in microglia knockout IL-10 mice

Abstract

Background Members of the transient receptor potential canonical (TRPC) protein family are widely distributed in the hippocampus of mammals and exert respective and cooperative influences on the functions of neurons. The relationship between specific TRPC subtypes and neuroinflammation is receiving increasing attention. Methods Using Cx3cr1CreERIL-10−/− transgenic mice and their littermates to study the relationship between TRPC channels and memory impairment. Results We demonstrated that Cx3cr1CreERIL-10−/− mice displayed spatial memory deficits in object location recognition (OLR) and Morris water maze (MWM) tasks. The decreased levels of TRPC4 and TRPC5 in the hippocampal regions were verified via reverse transcription polymerase chain reaction, western blotting, and immunofluorescence tests. The expression of postsynaptic density protein 95 (PSD95) and synaptophysin in the hippocampus decreased with an imbalance in the local inflammatory environment in the hippocampus. The number of cells positive for ionized calcium-binding adaptor molecule 1 (Iba1), a glial fibrillary acidic protein (GFAP), increased with the high expression of interleukin 6 (IL-6) in Cx3cr1CreERIL-10−/− mice. The nod-like receptor protein 3 (NLRP3) inflammasome was also involved in this process, and the cytokines IL-1β and IL-18 activated by NLRP3 were also elevated by western blotting. The co-localization of TRPC5 and calmodulin-dependent protein kinase IIα (CaMKIIα) significantly decreased TRPC5 expression in excitatory neurons. AAV9-CaMKIIα-TRPC5 was used to upregulate TRPC5 in excitatory neurons in the hippocampus. Conclusions The results showed that the upregulation of TRPC5 improved the memory performance of Cx3cr1CreERIL-10−/− mice related to inhibiting NLRP3 inflammasome-associated neuroinflammation. Graphical Abstract

IL-10 partly mediates the ability of MSC-derived extracellular vesicles to attenuate myocardial damage in experimental metabolic renovascular hypertension

“…Conversely, IL-10-KD-EVs failed to decrease inflammation either in vivo or in vitro . IL-10 is a potent anti-inflammatory cytokine with a crucial role in the inflammatory response and injury repair ( 36 – 38 ). Our observations implying that IL-10 is a central mediator of the anti-inflammatory properties of EVs in the myocardium are consistent with previous studies suggesting that IL-10-overexpressing MSCs increased autophagy and protected rats against traumatic brain injury-induced neuronal damage ( 39 ).…”

Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

“…The findings in the current study exclude a cellautonomous effect of heterozygous Nf1 loss on microglia. As such, Nf1 differs from other genes that directly affect microglia function through intrinsic mechanisms, such as Cx3cr1 [52,53], P2ry12 [27,61], Gabbr1 [19], Chrm3 [11], Apoe [28], Tgfbr2 [75], Bmal1 [66], Il6 [57], Il10 [31,70] or Bdnf [47]. It should, however, The number of intersected processes is plotted against their distance from the soma.…”

Post-traumatic stress disorder: the role of the amygdala and potential therapeutic interventions – a review

“…A link between TRPC subtypes and neuroinflammation is also evident from animal studies. Transgenic mice with IL-10 deficiency in microglial cells that express elevated levels of pro-inflammatory cytokines also exhibited decreased TRPC4 and TRPC5 in the hippocampus, and decreased TRPC5 in the PFC and amygdala when compared to wild-type control ( 66 , 67 ), suggesting a link between TRPC and neuroinflammation in stress-related brain areas. Considering the evidence implicating amygdala involvement in PTSD symptoms ( 24 ), the location of both TRPC4 and TRPC5 in the amygdala ( 22 , 59 , 60 ) and their link with local neuroinflammation ( 66 , 67 ), in addition to the reduced fear and anxiety demonstrated in knockout mice (TRPC4−/− rodents and TRPC5−/− rodents) ( 22 , 59 ), it is reasonable to hypothesize that dampening amygdala activation of the fear response by blocking these ion channels may reduce PTSD symptom severity.…”

“…TRPC4 and TRPC5 are homologous proteins that form ion channels involved in the regulation of neuronal growth, axon guidance, synaptic plasticity, and cellular excitability (60). Impairments in these cellular processes contribute to important brain functions, including working memory, hippocampal dysfunctions such as seizures, and fear responses (62,64,65). TRPC knockout mice (TRPC5−/−) exhibited diminished fear-related behaviors, indicating that TRPC5 plays a key role in fear responses in mice (22).…”