Memantine attenuates cognitive impairments after status epilepticus induced in a lithium-pilocarpine model.

The capability of memantine, a noncompetitive antagonist of the NMDA receptors, to prevent impairments of cognitive functions in rats was investigated in the lithium-pilocarpine model of epilepsy. After status epilepticus, rats exhibited impaired exploratory behavior and spatial memory, and a decline of extinction of orienting behavior. Memantine administration prevented these disturbances. Thus, the blockade of the NMDA receptors immediately after status epilepticus allowed prevention of the development of the possible cognitive impairments.

Impairment of exploratory behavior and spatial memory in adolescent rats in lithium-pilocarpine model of temporal lobe epilepsy.

Cognitive impairment in six-week -old rats has been studied in the lithium-pilocarpine model of adolescent temporal lobe epilepsy in humans. The pilocarpine-treated rats (n =21) exhibited (a) a decreased exploratory activity in comparison with control rats (n = 20) in the open field (OP) test and (b) a slower extinction of exploratory behavior in repeated OP tests. The Morris Water Maze (MWM) test showed that the effect of training was less pronounced in the pilocarpine-treated rats, which demonstrated disruption of predominantly short-term memory. Therefore, our study has shown that lithium-pilocarpine seizures induce substantial changes in exploratory behavior and spatial memory in adolescent rats. OP and MWM tests can be used in the search of drugs reducing cognitive impairments associated with temporal lobe epilepsy.

The domain of neuronal firing on a plane of input current and conductance.

The activation of neurotransmitter receptors increases the current flow and membrane conductance and thus controls the firing rate of a neuron. In the present work, we justified the two-dimensional representation of a neuronal input by voltage-independent current and conductance and obtained experimentally and numerically a complete input-output (I/O) function. The dependence of the steady-state firing rate on the input current and conductance was studied as a two-parameter I/O function. We employed the dynamic patch clamp technique in slices to get this dependence for the whole domain of two input signals that evoke stationary spike trains in a single neuron (Ω-domain). As found, the Ω-domain is finite and an additional conductance decreases the range of spike-evoking currents. The I/O function has been reproduced in a Hodgkin-Huxley-like model. Among the simulated effects of different factors on the I/O function, including passive and active membrane properties, external conditions and input signal properties, the most interesting were: the shift of the right boundary of the Ω-domain (corresponding to the exCitation block) leftwards due to the decrease of the maximal potassium conductance; and the reduction of the Ω-domain by the decrease of the maximal sodium concentration. As found in experiments and simulations, the Ω-domain is reduced by the decrease of extracellular sodium concentration, by cooling, and by adding slow potassium currents providing interspike interval adaptation; the Ω-domain height is increased by adding color noise. Our modeling data provided a generalization of I/O dependencies that is consistent with previous studies and our experiments. Our results suggest that both current flow and membrane conductance should be taken into account when determining neuronal firing activity.

Delayed effect of prenatal exposure to hypoxia on the susceptibility of rats to electric seizures.

We studied the delayed effects of prenatal exposure to hypoxia on the susceptibility of rats to seizures. The later was estimated using graded electroshock. The experiments were performed in two groups of 1.5-year-old male Wistar rats. The experimental group consisted of the animals that were exposed to hypoxia on day 14 of prenatal development, and the control group consisted of the animals that developed under the normal conditions. In the rats subjected to prenatal hypoxia, seizure episodes induced by weak currents in the range of 10-40 mA and their average duration were more pronounced as compared to the control animals.

A simple Markov model of sodium channels with a dynamic threshold.

Characteristics of action potential generation are important to understanding brain functioning and, thus, must be understood and modeled. It is still an open question what model can describe concurrently the phenomena of sharp spike shape, the spike threshold variability, and the divisive effect of shunting on the gain of frequency-current dependence. We reproduced these three effects experimentally by patch-clamp recordings in cortical slices, but we failed to simulate them by any of 11 known neuron models, including one- and multi-compartment, with Hodgkin-Huxley and Markov equation-based sodium channel approximations, and those taking into account sodium channel subtype heterogeneity. Basing on our voltage-clamp data characterizing the dependence of sodium channel activation threshold on history of depolarization, we propose a 3-state Markov model with a closed-to-open state transition threshold dependent on slow inactivation. This model reproduces the all three phenomena. As a reduction of this model, a leaky integrate-and-fire model with a dynamic threshold also shows the effect of gain reduction by shunt. These results argue for the mechanism of gain reduction through threshold dynamics determined by the slow inactivation of sodium channels.

[Properties of spontaneous and miniature excitatory postsynaptic currents of rat prefrontal cortex neurons].

Quantum analysis of postsynaptic currents is important for fundamental and applied studies of synaptic transmission. In the present work, we investigated the possibility of using the characteristics of spontaneous excitatory postsynaptic currents (EPSCs) for estimation of quantum parameters of excitatory synaptic transmission in different types of neurons from rat prefrontal cortex slices. By blocking spontaneous spiking activity in slices by tetrodotoxin, we showed that spontaneous and miniature EPSCs in prefrontal cortex neurons did not differ by their properties. Thereby, both spontaneous and miniature responses can be used for estimation of quantum parameters of excitatory synaptic transmission in this preparation. We also revealed that excitatory spontaneous responses of pyramidal cells were 2 times lower by amplitude, had twice lower the coefficient of variation and exhibited much slower kinetics than responses of the fast-spiking and regular-spiking interneurons. Possible mechanisms of these differences are considered.

[Morphofunctional changes in field CA1 of the rat hippocampus after pentylenetetrazole and lithium-pilocarpine induced seizures].

Animal models of epilepsy are very diverse and are used to elucidate the mechanisms underlying epileptogenesis and seizures. A single administration of pentylenetetrazole (PTZ) induces seizures, however it does not increase risk of further development of epilepsy. Pilocarpine immediately after injection evokes status epilepticus and after a latent period spontaneous convulsions develop in animals, i. e., the drug initiates the process of epileptogenesis. Assuming that in the PTZ model morphofunctional changes are mainly transient whereas changes in the lithium-pilocarpine (PC) model can indicate development of the brain epileptizationm, we compared morphological and functional characteristics in field CA1 of the hippocampus in a control and two groups of experimental animals 24 h after administration of convulsants. We revealed changes specific to the PC model and indicating the process of neurodegeneration: a decrease of the cell density, an altered NeuN expression, and an increase of the proapoptotic protease caspase-3 activity. A characteristic feature of the PTZ model was appearance of hyperchromic neurons with normal viability. In both models expression of the excitatory amino acids carrier EAAT1 increased by about 40% as compared to control. These morphofunctional correlates of reversible changes in the nervous tissue, caused by the convulsive state, and the early disturbances leading to the long-term brain epileptization can be used as indicators for evaluating therapeutic potential of novel anticonvulsive drugs.

[The effect of ionotropic glutamate receptor antagonist on pentylenetetrazole-indused seizures in Krushinsky-Molodkina rats].

Krushinsky-Molodkina (KM) rats exhibit inherited susceptibility to audiogenic seizures and auditory stimuli induce generalized tonic-clonic seizures that resemble human epilepsy. The aim of this study was to compare the neurological manifestations of pentylenetetrazole (PTZ)-induced seizures in Wistar and KM rats to clarify the contribution of inherited susceptibility to audiogenic seizures, and to assess the anticonvulsant activity of NMDA receptor blockers memantine and IEM-1921 (1-phenylcyclohexylamine) in the PTZ-induced seizure model in KM rats. KM rats exhibited increased seizure severity relative to Wistar rats, and the death of KM rats was observed in 2.1 times more likely. Both NMDA receptor blockers showed anticonvulsant activity in the PTZ-induced seizure model, however IEM-1921 was more potent than memantine. IEM-1921 reduced the average intensity of the seizures by 2 points on a 5-point scale, and the total duration of generalized seizures was decreased by 41 times. IEM-1921 completely prevented the death of animals, while memantine only slightly decreased the mortality (68% in control conditions vs. 50% with administration of memantine). The results of the present study suggest that NMDA receptors are involved in the molecular mechanisms of seizures of different etiologies.

[Synchronization of secretion of the evoked transmitter quanta as mechanism of the facilitating action of sympathomimetics]. / Sinkhronizatsiia vyzvannoi sekretsii kvantov mediatora kak mekhanizm oblegchaiushchego deistviia simpatomimetikov.

Noradrenaline, isoproterenol, dobutamine were found to modulate kinetics of quanta secretion so as to synchronize the transmitter release. This effect could be prevented with blocking agents of beta-adrenoreceptor (atenolol, propranolol). Activators of beta-adrenoreceptors klonidine and phenylephrine did not change the kinetics of quanta secretion, whereas phentolamine did not affect the synchronizing effect of noradrenaline. The change in the time course of the secretion induced by noradrenaline increased the end-plate current amplitude. There seems to exist a specific presynaptic mechanism involving beta-adrenoreceptors for facilitation of effects of sympathomimetics.