Neuronal CXCL10/CXCR3 Axis Mediates the Induction of Cerebral Hyperexcitability by Peripheral Viral Challenge.

Tiffany J Petrisko,Vishnu Suppiramaniam,Hao Hong,Jenna Bloemer,Priyanka D Pinky,Sriraja Srinivas,Yifeng Du,Miranda N Reed,Ryan T Heslin,Sharay E Setti,Gregory W Konat

doi:10.3389/fnins.2020.00220

Abstract

Peripheral infections can potently exacerbate neuropathological conditions, though the underlying mechanisms are poorly understood. We have previously demonstrated that intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC) induces a robust generation of CXCL10 chemokine in the hippocampus. The hippocampus also features hyperexcitability of neuronal circuits following PIC challenge. The present study was undertaken to determine the role of CXCL10 in mediating the development of hyperexcitability in response to PIC challenge. Briefly, young female C57BL/6 mice were i.p. injected with PIC, and after 24 h, the brains were analyzed by confocal microscopy. CXCL10 staining of neuronal perikarya and a less intense staining of the neuropil was observed in the hippocampus and cortex. CXCL10 staining was also evident in a subpopulation of astrocytes, whereas microglia were CXCL10 negative. CXCR3, the cognate receptor of CXCL10 was present exclusively on neurons, indicating that the CXCL10/CXCR3 axis operates through an autocrine/paracrine neuronal signaling. Blocking cerebral CXCR3 through intracerebroventricular injection of a specific inhibitor, AMG487, abrogated PIC challenge-induced increase in basal synaptic transmission and long-term potentiation (LTP), as well as the reduction of paired-pulse facilitation (PPF), in the hippocampus. The PIC-mediated abolishment of hippocampal long-term depression (LTD) was also restored after administration of AMG487. Moreover, CXCR3 inhibition attenuated seizure hypersensitivity induced by PIC challenge. The efficacy of AMG487 strongly strengthens the notion that CXCL10/CXCR3 axis mediates the induction of cerebral hyperexcitability by PIC challenge.

Highlights

Peripheral infections are important comorbid factors for the major neuropathological conditions
We have demonstrated that polycytidylic acid (PIC) challenge induces hyperexcitability of neuronal networks as seen from a profound increase in the basal synaptic transmission and long term potentiation (LTP) in hippocampal slices (Hunsberger et al, 2016), as well as from hypersusceptibility to kainic acid (KA)-induced status epilepticus (Kirschman et al, 2011; Michalovicz and Konat, 2014; Hunsberger et al, 2017)
Immunofluorescent analysis performed 24 h after PIC challenge revealed intense CXCL10 staining throughout the brain, whereas a negligible staining was observed in the brain of salineinjected mice (Figure 1A)

Summary

Introduction

Peripheral infections are important comorbid factors for the major neuropathological conditions. Because neuronal hyperexcitability is an invariable feature of the major neuropathologies (Esclapez et al, 1999; Lehmann et al, 2000; Buljevac et al, 2002; Holmes et al, 2003; Caramia et al, 2004; Palasik et al, 2005; Tellez-Zenteno et al, 2005; Scheid and Teich, 2007; Verrotti et al, 2009; Khedr et al, 2011; Penzes et al, 2011; Rossi et al, 2012; Scharfman, 2012; Huynh et al, 2013; Yener and Basar, 2013; Eikermann-Haerter, 2014), it might provide a mechanistic link for the exacerbating effects of peripheral inflammation on disease progression

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Conclusion