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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 (10 8 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 ∆RVG (deleted PBM). Furthermore, RVG and ∆RVG strengthened paired pulse facilitation.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 post-synaptic mechanisms to alter synaptic function. Further studies are needed to elucidate the underlying mechanisms.

Rabies is a life-threatening viral infection of the brain. Rabies virus (RABV) merely infects excitable cells including neurons provoking drastic behaviors including negative emotional memories. RABV glycoprotein (RVG) plays a critical role in RABV pathogenesis. RVG interacts with various cytoplasmic PDZ (PSD-95/Dlg/ZO-1) containing proteins through its PDZ binding motif (PBM). PTZ domains have crucial role in formation and function of signal transduction.Hippocampus is one of the cerebral regions that contains high load of viral antigens. We examined impact of RVG expression in the dorsal hippocampus on aversive as well as spatial learning and memory performance in rats.Two μl of the lentiviral vector (~10 8 T.U. /ml) encoding RVG or ∆RVG (deleted PBM) genomes was microinjected into the hippocampal CA1. After one week, rat's brain was cross-sectioned and RVG/∆RVG-expressing neuronal cells were confirmed by fluorescent microscopy. Passive avoidance and spatial learning and memory were assessed in rats by Shuttle box and Morris water maze (MWM).In the shuttle box, both RVG and ∆RVG decreased the time spent in the dark compartment compared to control (p<0.05). In MWM, RVG and ∆RVG did not affect the acquisition of spatial task. RVG-expressing rats reached the platform position in the probe test sooner than control and ∆RVG groups (p<0.05). Rats expressing ∆RVG significantly swam farther from the hidden platform than RVG group (p<0.05).Our data indicate RVG expression in the hippocampus strengthens aversive and spatial learning and memory performance. The boosting effect on spatial but not avoidance memory is mediated through PBM.

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Traumatic brain injury (TBI) is responsible for 5% of all epilepsy cases, which are known as post-traumatic epilepsy. Macrophage/microglia are key players in TBI pathogenesis. They are activated after TBI, transform to inflammatory phenotype (M1) and trigger neuroinflammation, which provokes epileptogenesis. Interleukin-4 (IL-4) is a well-known polarizer of macrophage/microglia to the anti-inflammatory phenotype (M2). We tested the effect of IL-4 on the rate of epileptogenesis, brain expression of inflammatory and anti-inflammatory cytokines, and the lesion size in traumatic rats. Trauma was exerted to temporo-parietal cortex of rats by Controlled Cortical Impact. Thereafter, rats received a single dose (100ng/rat) of IL-4 through intracerebroventricular injection. After 24h, pentylenetetrazole (PTZ) kindling started and development of generalized seizures was recorded. Level of TNF-α, TGF-β, IL-10, and arginase-1 (Arg-1) was measured in the brain by immunoblotting at 6h, 12h, 24h, 48h, and 5 days after TBI. The lesion size and cell survival were determined by staining. Traumatic rats were kindled by 5±1 PTZ injections (significantly less than 11±2 injections of control and sham-operated rats, p<0.001). IL-4 did not change kindling rate in sham-operated rats but inhibited acceleration of kindling rate in traumatic rats (13±1 PTZ injections, p<0.001). IL-4 decreased post-TBI overexpression of TNF-α (6h, p<0.001) whereas upregulated post-TBI expression of TGF-β (48h, p<0.001), IL-10 (24h, p<0.05; 48h, p<0.01), and Arg-1 (24h, p<0.001). IL-4 decreased lesion volume and number of dead neurons. IL-4 suppresses TBI-induced acceleration of epileptogenesis in rats by directing macrophage/microglia to the anti-inflammatory M2 phenotype and inhibition of neuronal death.