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Lentiviral Expression of Rabies Virus Glycoprotein in the Rat Hippocampus Strengthens Synaptic Plasticity

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Abstract

Rabies virus (RABV) is a neurotropic virus exclusively infecting neurons in the central nervous system. RABV encodes five proteins. Among them, the viral glycoprotein (RVG) plays a key role in viral entry into neurons and rabies pathogenesis. It was shown that the nature of the C-terminus of the RABV G protein, which possesses a PDZ-binding motif (PBM), modulates the virulence of the RABV strain. The neuronal protein partners recruited by this PBM may alter host cell function. This study was conducted to investigate the effect of RVG on synaptic function in the hippocampal dentate gyrus (DG) of rat. Two μl (108 T.U./ml) of the lentiviral vector containing RVG gene was injected into the DG of rat hippocampus. After 2 weeks, the rat’s brain was cross-sectioned and RVG-expressing cells were detected by fluorescent microscopy. Hippocampal synaptic activity of the infected rats was then examined by recording the local field potentials from DG after stimulation of the perforant pathway. Short-term synaptic plasticity was also assessed by double pulse stimulation. Expression of RVG in DG increased long-term potentiation population spikes (LTP-PS), whereas no facilitation of LTP-PS was found in neurons expressing δRVG (deleted PBM). Furthermore, RVG and δRVG strengthened paired-pulse facilitation. Heterosynaptic long-term depression (LTD) in the DG was significantly blocked in RVG-expressing group compared to the control group. This blockade was dependent to PBM motif as rats expressing δRVG in the DG-expressed LTD comparable to the RVG group. Our data demonstrate that RVG expression facilitates both short- and long-term synaptic plasticity in the DG indicating that it may involve both pre- and postsynaptic mechanisms to alter synaptic function. Further studies are needed to elucidate the underlying mechanisms.

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adapted from atlas of Paxinos and Watson showing the position of the stimulating electrodes in the perforant pathway and recording electrodes in dentate gyrus. b A fluorescent image shows location of recording electrodes and transduced cells in the dentate gyrus. c Input and output curves indicate no difference of normalized responses to seven stimulus intensities between groups. d Baseline responses to the 50% maximum of intensity during 30 min are more prominent in rats expressing RVG (n = 10) in dentate gyrus, compared to control (n = 11) and δRVG (n = 10) groups. *p < 0.05 and **p < 0.01 compared to the control group. #p < 0.05 and ##p < 0.01 compared to δRVG group

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Acknowledgements

This research is supported by Grant No, 868 from Pasteur Institute and is a part of PhD thesis of Soheil Ghassemi.

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HGP and MS involved in study concept and design and study supervision, participated in experimental design and statistical analysis, and obtained funding: SGH, TA, HMD, and SA participated in acquisition of the data. HGP, KA, and MS performed analysis and interpretation of the data. HGP, CP, ML, AG, NN, and MS drafted the manuscript. MS involved in administrative, technical, and material support. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Hamid Gholami Pourbadie or Mohammad Sayyah.

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All animal experiments were carried out in accordance with the Review Board and Ethics Committee of Pasteur Institute (Authorization code 93-0201-785, 22 April 2014) and conform to the European Communities Council Directive 2010-63-EU.

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Ghassemi, S., Asgari, T., Mirzapour-Delavar, H. et al. Lentiviral Expression of Rabies Virus Glycoprotein in the Rat Hippocampus Strengthens Synaptic Plasticity. Cell Mol Neurobiol 42, 1429–1440 (2022). https://doi.org/10.1007/s10571-020-01032-9

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