Genetic Background Influence on Hippocampal Synaptic Plasticity: Frequency-Dependent Variations between an Inbred and an Outbred Mice Strain.

For almost half a century, acute hippocampal slice preparations have been widely used to investigate anti-amnesic (or promnesic) properties of drug candidates on long-term potentiation (LTP)-a cellular substrate that supports some forms of learning and memory. The large variety of transgenic mice models now available makes the choice of the genetic background when designing experiments crucially important. Furthermore, different behavioral phenotypes were reported between inbred and outbred strains. Notably, some differences in memory performance were emphasized. Despite this, investigations, unfortunately, did not explore electrophysiological properties. In this study, two stimulation paradigms were used to compare LTP in the hippocampal CA1 area of both inbred (C57BL/6) and outbred (NMRI) mice. High-frequency stimulation (HFS) revealed no strain difference, whereas theta-burst stimulation (TBS) resulted in significantly reduced LTP magnitude in NMRI mice. Additionally, we demonstrated that this reduced LTP magnitude (exhibited by NMRI mice) was due to lower responsiveness to theta-frequency during conditioning stimuli. In this paper, we discuss the anatomo-functional correlates that may explain such hippocampal synaptic plasticity divergence, although straightforward evidence is still lacking. Overall, our results support the prime importance of considering the animal model related to the intended electrophysiological experiments and the scientific issues to be addressed.

Efficacy of anticonvulsant substances in the 6Hz seizure test: Comparison of two rodent species.

Usually performed in the mouse, the 6Hz seizure test is used for screening potential new anticonvulsant substances against complex partial seizures. Nevertheless, advanced models of temporal lobe epilepsy (TLE) are more often performed in rats, so that possible species-related differences may complicate the development of anticonvulsant substances. The aim of the present study was to evaluate the feasibility of adapting the 6Hz test in the rat. We first compared the effects of increasing current intensities for inducing seizures in the mouse and in the rat. This step was followed by the evaluation of the activity of anticonvulsant substances. Animals received an electrical stimulation with a constant current via corneal electrodes. The seizure was characterized by the presence of forelimb clonus immediately after stimulation. Spontaneous locomotion was evaluated following the 6Hz test. In the rat, the forelimb seizure score was intensity-dependently increased and seizures were observed in all animals tested at 44mA. In the mouse, the seizures were of lower magnitude and they were not observed in all mice stimulated at 44mA. In both species, levetiracetam (LEV) clearly decreased the forelimb seizure score over the dose-range 100-300mg/kg without affecting locomotion. Valproate (VPA) displayed anticonvulsant activity at 200mg/kg and fully protected both species at 300mg/kg, a dose producing sedative effects in the mouse. Phenytoin (PHT) showed slight to moderate anticonvulsant activity at 100mg/kg in the mouse and at 60 and 100mg/kg in the rat without modifying locomotor activity. Lamotrigine (LTG) partially antagonized forelimb seizure at 60mg/kg in the mouse and at 30-60mg/kg in the rat, but it induced clear motor impairments at high dose in both species. Our data suggest that in the 6Hz test, the magnitude and the nature of seizures differed between the mouse and the rat for a given current intensity. Nevertheless, the pharmacological profile of anticonvulsant substances was similar in both species for the 4 substances tested. Dose-dependent efficacy of LEV and VPA was observed and LTG and PHT also showed anticonvulsant activity, even though the magnitude of the effects remained moderate for these two last substances. The 6Hz test in the rat therefore appears as a useful model which may be performed prior to follow-up models of partial seizures performed in the same species.

Evaluation of pro-convulsant risk in the rat: spontaneous and provoked convulsions.

INTRODUCTION: The aim of the present study was to evaluate the utility of different tests performed in the absence or presence of factors promoting seizures in order to evaluate the pro-convulsant effects of drugs. We studied the effects of theophylline in the rat since this is a well-known pro-convulsant substance in humans. METHODS: The occurrence of spontaneous convulsions following administration of theophylline was evaluated by observation in the Irwin Test and by measuring brain activity using video-EEG recording in conscious telemetered animals. Theophylline was also tested in the electroconvulsive shock (ECS) threshold and pentylenetetrazole (PTZ)-induced convulsions tests, two commonly used models of provoked convulsions. RESULTS: In the Irwin test, theophylline induced convulsions in 1 out of 6 rats at 128 mg/kg. Paroxysmal/seizure activity was also observed by video-EEG recording in 4 out of the 12 animals tested at 128 mg/kg, in presence of clonic convulsions in 3 out of the 4 rats. Paroxysmal activity was observed in two rats in the absence of clear behavioral symptoms, indicating that some precursor signs can be detected using video-EEG. Clear pro-convulsant activity was shown over the dose-range 32-128 mg/kg in the ECS threshold and PTZ-induced convulsions tests. DISCUSSION: Evaluation of spontaneous convulsions provides information on the therapeutic window of a drug and the translational value of the approach is increased by the use of video-EEG. Tests based on provoked convulsions further complement the evaluation since they try to mimic high risk situations. Measurement of both spontaneous and provoked convulsions improves the evaluation of the pro-convulsant risk of novel pharmacological substances.

Combined therapeutic strategy using erythropoietin and mesenchymal stem cells potentiates neurogenesis after transient focal cerebral ischemia in rats.

Many studies showed beneficial effects of either erythropoietin (EPO) or mesenchymal stem cells (MSCs) treatment in cerebral ischemia. In addition to a neuroprotective role, not only EPO but also MSC favors neurogenesis and functional recovery. In an attempt to further improve postischemic tissue repair, we investigated the effect of a systemic administration of MSC, in the presence or not of EPO, on neurogenesis and functional recovery in a transient focal cerebral ischemia model in the adult rat. Twenty-four hours after ischemia, the rats were divided into four groups, namely vehicle, MSC, EPO, and MSC+EPO, and received a single intravenous injection of MSC (2 x 10(6) cells) and/or a repeated intraperitoneal administration of EPO (1,000 UI/kg) for 3 days. The lesion volume, the MSC outcome, neurogenesis, and functional recovery were assessed 51 days after ischemia. The results showed that cellular proliferation and neurogenesis were increased along the lateral ventricle wall in the MSC+EPO group, whereas no significant effect was observed in groups receiving MSC or EPO alone. This effect was accompanied by an improvement of mnesic performances. Mesenchymal stem cells expressing neuronal or glial markers were detected in the ischemic hemisphere. These results suggest that EPO could act in a synergistic way with MSC to potentiate the postischemic neurogenesis.