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Sepsis survivors frequently develop late cognitive impairment. Because little is known on the mechanisms of post-septic memory deficits, there are no current effective approaches to prevent or treat such symptoms. Here, we subjected mice to severe sepsis induced by cecal ligation and puncture (CLP) and evaluated the sepsis-surviving animals in the open field, novel object recognition (NOR), and step-down inhibitory avoidance (IA) task at different times after surgery. Post-septic mice (30 days post-surgery) failed in the NOR and IA tests but exhibited normal performance when re-evaluated 45 days after surgery. Cognitive impairment in post-septic mice was accompanied by reduced hippocampal levels of proteins involved in synaptic plasticity, including synaptophysin, cAMP response element-binding protein (CREB), CREB phosphorylated at serine residue 133 (CREBpSer), and GluA1 phosphorylated at serine residue 845 (GluA1pSer). Expression of tumor necrosis factor α (TNF-α) was increased and brain insulin signaling was disrupted, as indicated by increased hippocampal IRS-1 phosphorylation at serine 636 (IRS-1pSer) and decreased phosphorylation of IRS-1 at tyrosine 465 (IRS-1pTyr), in the hippocampus 30 days after CLP. Phosphorylation of Akt at serine 473 (AktpSer) and of GSK3 at serine 9 (GSK3βpSer) were also decreased in hippocampi of post-septic animals, further indicating that brain insulin signaling is disrupted by sepsis. We then treated post-septic mice with liraglutide, a GLP-1 receptor agonist with insulinotropic activity, or TDZD-8, a GSK3β inhibitor, which rescued NOR memory. In conclusion, these results establish that hippocampal inflammation and disrupted insulin signaling are induced by sepsis and are linked to late memory impairment in sepsis survivors.

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Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a co-morbidity and a risk factor for Alzheimer’s disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes infndc5expression in post-mortem brain tissue from MDD individuals and mouse models of depression. We found decreasedfndc5expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that induction of depressive-like behavior in male mice by lipopolysaccharide decreasedfndc5expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increasedfndc5expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in alteredfndc5expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increasedfndc5gene expression in the mouse frontal cortex. Results indicate a region-specific modulation offndc5in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortexfndc5expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction infndc5mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathological mechanism between MDD and AD.Significance StatementMajor depressive disorder (MDD) is a major cause of disability in humans. Physical exercise reduces the incidence and severity of MDD, but molecular mechanisms are elusive. One of the pleiotropic actions of exercise alludes to the increased production and circulation of irisin, a myokine cleaved from fibronectin type III domain-containing protein 5 (FNDC5) that mediates some benefits of exercise in the brain. Here, we observed reducedfndc5expression in post-mortem samples of dorsolateral prefrontal cortex from patients with MDD. In the mouse frontal cortex, modulation offndc5was variable across models of depressive-like behavior. Our findings indicate reducedfndc5expression in MDD with discordant results in mice and stimulate further research on the roles of brain FNDC5/irisin in MDD.

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Impaired synaptic plasticity and progressive memory deficits are major hallmarks of Alzheimer's disease (AD). Hippocampal mRNA translation, required for memory consolidation, is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), ameliorated the inhibition of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-b; oligomers (AbOs) in mice. Furthermore, systemic treatment with (2R,6R)-hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine, prevented deficits in hippocampal mRNA translation, long-term potentiation (LTP) and memory induced by AbOs in mice. HNK activated hippocampal signaling by extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 (S6), which promote protein synthesis and synaptic plasticity. S6 phosphorylation instigated by HNK was mediated by mTOR in hippocampal slices, while rescue of hippocampal LTP and memory in HNK-treated AbO-infused mice depended on ERK1/2 and, partially, on mTORC1. Remarkably, treatment with HNK corrected LTP and memory deficits in aged APP/PS1 mice. RNAseq analysis showed that HNK reversed aberrant signaling pathways that are upregulated in APP/PS1 mice, including inflammatory and hormonal responses and programmed cell death. Taken together, our findings demonstrate that upregulation of mRNA translation corrects deficits in hippocampal synaptic plasticity and memory in AD models. The results raise the prospect that HNK could serve as a therapeutic to reverse memory decline in AD.

BackgroundBrain accumulation of the amyloid‐β peptide (Aβ) is a pathological hallmark of Alzheimer’s disease (AD). Considerable evidence indicates that soluble Ab oligomers (AβOs) cause synapse failure/loss and cognitive decline in AD. Evidence further indicates that the ubiquitin‐proteasome system (UPS) is inhibited in AD brains, likely leading to impaired synaptic plasticity and memory. However, the mechanisms underlying UPS dysfunction in AD remain to be elucidatedMethodHere, we investigated proteasome activity in primary hippocampal cultures and in isolated hippocampal synaptosomes from mice that received an intracerebroventricular (i.c.v.) infusion of AβOs. We further investigated the possible protective actions of UCH‐L1, an enzyme that enhances proteasome‐mediated degradation of target proteins, against the impact of AβOs on hippocampal neurons and memory.ResultExposure to AβOs resulted in decreased proteasome activity in primary hippocampal cultures and in isolated hippocampal synaptosomes. Synaptosomes isolated from the hippocampi of AβO‐infused mice were also inhibited compared to hippocampal synaptosomes from control, vehicle‐infused mice. Treatment with exogenous recombinant UCH‐L1 prevented oxidative stress in AβO‐exposed hippocampal neurons and memory deficit in AβO‐infused mice.ConclusionThese results indicate that AβOs inhibit the proteasome, notably at synapses, and suggest that boosting proteasomal proteolysis prevents AβO‐induced neuronal damage and memory deficit.