Unfolded protein response and associated alterations in toll-like receptor expression and interaction in the hippocampus of restraint rats

Abstract

Recent evidence suggests that the cellular response to stress often elicits the unfolded protein response (UPR), which has an active role in major depression in emotionally relevant regions of the brain, such as the hippocampus. Much of the UPR activity has been found to be coalesced with the pro-inflammatory environment of the depressed brain. Specifically, downstream transcriptions of pro-inflammatory cytokines and increased regulation of candidate inflammatory mediators, such as toll-like receptors (TLRs), are promoted by the UPR. The present study examined the hippocampus associated expression profile of Tlr genes and their interaction with the UPR chaperone GRP94 in stress-induced rodent model of depression (restraint stress model). Also, the expression status of UPR related genes was evaluated in hippocampus using the same model. mRNA and protein levels of Tlr and UPR associated genes were examined by qRT-PCR and Western blot, respectively. Co-immunoprecipitation (Co-IP) method was used to determine the direct interaction between TLRs with GRP94 in depressed rat brain. The results showed that both UPR (Xbp-1, its spliced variant sXbp-1, Atf-6, Chop, and Grp94) and Tlr (2, 3, 4, 7 and 9) genes were significantly upregulated in the hippocampi of rats who were exposed to restraint stress. Similar upregulation was observed in the protein levels of the above-mentioned TLRs and the UPR chaperone protein GRP94 as well as total and phosphorylated forms of sensor proteins IRE1α and PERK. Further, a significantly increased interaction was observed between GRP94 and the activated TLR proteins. Since, increased inflammatory activity in vulnerable areas like hippocampus is coherently associated with depressed brain; our present data suggest that the UPR may be an integral part of increased activity of inflammatory regulations in depression.

Chronic Testosterone Increases Impulsivity and Influences the Transcriptional Activity of the Alpha-2A Adrenergic Receptor Signaling Pathway in Rat Brain

“…The single-stranded cDNA was prepared as described previously [28]. Following the preparation of mRNA specific first strand cDNA, 1 μg total RNA was reverse transcribed using M-MLV Reverse Transcriptase (Invitrogen, NY, USA) and oligo (dT) primer.…”

Intra-CA1 Administration of Minocycline Alters the Expression of Inflammation-Related Genes in Hippocampus of CCI Rats

“…TLR1 expression in the hippocampus was increased in the neurons, microglia, and astrocytes in seizure mice (Wang et al, 2015). TLR (2, 3, 4, 7, and 9) expression was upregulated in the hippocampus of restraint stressed rats (Timberlake et al, 2018). TLR2 and TLR4 in the rat hippocampus are related to the lipopolysaccharide (LPS)-induced neuron cell death (He et al, 2013; Henry et al, 2014).…”

Molecular pathology associated with altered synaptic transcriptome in the dorsolateral prefrontal cortex of depressed subjects

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