Overinhibition mediated by parvalbumin interneurons in the medial prefrontal cortex might contribute to LPS-induced...

Accumulating evidence suggests that an imbalance between excitation and inhibition plays a significant role in depression, yet its role in neuroinflammation-induced depression remains unclear. In this study, we aimed to explore the intrinsic mechanism underlying neuroinflammation-induced excitation/inhibition imbalance in a mouse model of depression.

In our study, depression-like behavior was induced in cohorts of male C57BL/6J mice through repeated injections of lipopolysaccharide (LPS, 0.5 mg/kg, daily, i.p.) for seven consecutive days. Mice were injected with either saline or esketamine (10 mg/kg, i.p.) for three consecutive days.The sucrose preference test (SPT) and tail suspension test (TST) were conducted to assess depressive-like behavior induced by LPS. The open field test (OFT) was conducted to evaluate the locomotor activity of mice. Subsequently, samples from the medial prefrontal cortex (mPFC) of some cohorts were harvested for immunofluorescence assays or western blotting analyses of VGAT, VGLUT2, CamkII, parvalbumin (PV), and somatostatin (SST). Calcium signal fiber photometry, whole-cell patch-clamp recordings and two-photon calcium imaging (2PCI) were utilized to determine the excitability of pyramidal neurons in the mPFC. Inactivation of PV interneurons was achieved through a chemogenetic approach.

Compared with the control group, LPS-induced mice exhibited a significant decrease in sucrose preference and an increase in immobility time of TST. In the OFT, compared with the control group, LPS-treated mice showed a significant reduction in total distance traveled. We identified that the expressions of VGAT and PV were increased in the mPFC of LPS-induced mice, whereas the expressions of VGLUT2 and SST showed no significant difference between two groups. Fiber photometry, electrophysiological recordings, and 2PCI collectively revealed a reduction in the activity of pyramidal neurons in the mPFC. Furthermore, chemogenetic inactivation of PV interneurons in the mPFC alleviated LPS-induced depression-like behavior. Administration of esketamine could reverse the elevated expression of PV and enhanced neuronal excitability in the mPFC.

It suggests that PV interneurons mediated-overinhibition in the mPFC might play a key role in LPS-induced depression-like behavior in mice.