Sepsis induced cognitive impairments by disrupting hippocampal parvalbumin interneuron-mediated inhibitory network via a D4-receptor mechanism

Abstract

Patients who suffer sepsis often develop cognitive impairments, yet the underlying mechanisms largely remain to be elucidated. Increasing evidence has suggested that parvalbumin (PV) interneurons are required for the synchronization of neural activities and higher brain processes, whereas its dysfunction is implicated in many psychiatric disorders. In the present study, we examined the role of hippocampal PV interneuron-mediated inhibitory network in a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP) and also explored the underlying mechanism. Here we showed that CLP-induced cognitive impairments, which were accompanied by significantly decreased expressions of PV and dopamine 4 (D4) receptor, decreased slow γ oscillation band, and reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs). Notably, D4 receptor agonist RO-10-5824 treatment was able to reverse most of these abnormities. In summary, our study suggests that sepsis might disrupt PV interneuron-mediated network function that is dependent on the D4 receptor, leading to abnormal γ oscillation and consequent cognitive impairments.

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

“…A well-trained investigator who was blinded to animal grouping performed the behavioral tests including the open field test (OFT at P45), elevated plus maze (EPM at P46), sucrose preference test (SPT at P47), and forced swim test (FST at P50) as we described previously (Ji et al, 2020). Behavioral testing was carried out in the same order for all rats during the light phase of the circadian cycle (09:30-14:00 h).…”

Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice

“…This has been attributed to DA simultaneously reducing spontaneous firing and increasing evoked firing in PV-expressing interneurons ( Tierney et al, 2008 ; Furth et al, 2013 ), which increases temporal precision and synchronization of fast-spiking interneuron firing ( Andersson et al, 2012a ), crucial in γ oscillations. Interestingly, sepsis causes reduced γ oscillation and consequent cognitive impairments via a reduction in DR4 and PV-expressing interneuron activity ( Ji et al, 2020 ). The signaling pathway downstream of DR4 activation is complex and involves synergistic action with the Neuregulin/ErbB4 signaling ( Andersson et al, 2012b ).…”

Parvalbumin interneuron-mediated neural disruption in an animal model of postintensive care syndrome: prevention by fluoxetine

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