Critical reviews in neurobiology最新文献

Acute cocaine toxicity is frequently associated with seizures. The mechanisms underlying the convulsant effect of cocaine are not well understood. Previously, we have shown that cocaine depresses whole-cell current evoked by gamma-aminobutyric acid (GABA) in hippocampal neurons freshly isolated from rats. Cocaine's effect was voltage-independent and concentration-dependent. In the present study, using whole-cell patch-clamp recording on rat neurons freshly isolated from hippocampus, we examined the intracellular mechanisms involved in cocaine's action. Increasing intracellular Ca(2+) concentration ([Ca]i) from 0.01 to 5 microM strongly increased the depressant effect of cocaine. By contrast, 1-[N, O-bis (5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), a specific antagonist of Ca/calmodulin-dependent protein kinase (CaMKII), attenuated or enhanced cocaine's action in different neurons: in three out of nine neurons dialysed with 5 microM KN-62,1 mM cocaine depressed GABA current by only 33%, but in another three out of nine neurons, cocaine depressed GABA current by as much as 83%. Chelerythrine (a specific CaCa(2+)/phospholipid-dependent protein kinase C [PKC] antagonist) had minimal effect on cocaine's action. We suggest that cocaine induces an increase in [Ca]i, which stimulates phosphatase activity and thus leads to dephosphorylation of GABA receptors. This dephosphorylation-mediated disinhibitory action may play a role in cocaine-induced convulsant states.

Inflammation is a defense reaction against diverse insults that serves to remove noxious agents and to limit their detrimental effects. There is increasing evidence that post-ischemic inflammation plays an important role in brain ischemia. However, whether inflammatory processes are deleterious or beneficial to recovery is presently a matter of debate and controversy. Experimentally and clinically, stroke is followed by an acute and a prolonged inflammatory response characterized by the production of inflammatory cytokines, leukocyte and monocyte infiltration in the brain, and the activation of resident glial cells. These events may contribute to ischemic brain injury. Several groups report conflicting results regarding the role of inflammation and effects of anti-inflammatory treatments in cerebral ischemia. Experimental studies employing knockout mice for different cytokines and chemokines provide only partial answers. This highlights the importance of clarifying the role of the immune response in pathological changes at the site of ischemic lesions in the brain. Here, we describe dual effects of the brain's inflammatory response and new evidence for a neuroprotective role of proliferating microglial cells in ischemia. In addition, we discuss a potential role of post-ischemic inflammation in brain regeneration and modulation of synaptic plasticity.

Diffusion of transmitters in the synaptic cleft critically influences synaptic efficacy by affecting both the amplitude and the time course of quantal events, but the value of the diffusion constant is speculative. In this study, we use molecular dynamics simulations to determine how the spatial confinement and membrane charges affect the diffusion constants of glutamate- and water as well as general properties of their diffusion. The synaptic cleft is represented as the space enclosed by two single-wall carbon sheets. Both water and especially glutamate are concentrated near the pore wall, where the concentration of glutamate can reach 30-50 times the mean value and the concentration of water can reach 2-8 times the mean value. Such spatial profiles of glutamate contradict the classical notions of diffusion on which both continuous and Monte Carlo simulations are built. The layering of glutamate- and water molecules suggests that the interfacial glutamate-cleft wall (or water-cleft wall) interactions may critically regulate their diffusion in the cleft. Indeed, the effective longitudinal diffusion constant of glutamate is steeply dependent on the cleft width, but only when the cleft is very narrow (< 5 nm). Therefore, even for a cleft as narrow as at the glutamatergic synapse in the central nervous system, the effective diffusion constant of glutamate will not be much lower than free diffusion in the bulk solution due to confinement. The effective diffusion constant of water is considerably less sensitive to cleft width over the same range of cleft widths than is glutamate, but is also higher than that of glutamate. Finally, the layering of glutamate and water and their effective diffusion constants are largely independent of how the cleft wall is charged. In conclusion, in the confined space of the synaptic cleft, glutamate is layered near the wall. Consequently, its diffusion constant becomes dependent on the cleft width. However, the diffusion of glutamate is slower than its free diffusion in water only if the cleft is very narrow. If the width of the cleft is consistent with that determined by morphometric studies in the central nervous system, glutamate diffusion should not be slowed by confinement and is thus likely to be similar to that in free solution.

Homeostatic plasticity is an important physiological process in the mammalian nervous system. In this review, we discuss methodological and mechanistic similarities and differences in cortical and hippocampal studies of homeostatic plasticity. Although there are many similarities, there are also region-specific differences in the effects and/or mechanisms that regulate homeostatic plasticity in these two regions. In this review, we propose a new experimental paradigm to study homeostatic plasticity that may address some unanswered questions in the field.

Early in development, network activity in the hippocampus is characterized by giant depolarizing potentials (GDPs). These potentials consist of recurrent membrane depolarizations with superimposed fast action potentials separated by quiescent intervals. They are generated by the interplay of glutamate and gamma-aminobutyric acid (GABA) that, in the immediate postnatal period, is depolarizing and excitatory. Here, we review some recent data concerning the functional role of GDPs in shaping synaptic currents at low-probability mossy-fiber (MF)-CA3 synapses. A pairing procedure was used to correlate GDPs-associated calcium increase in the postsynaptic cell with stimulation of afferent inputs. The pairing protocol caused the appearance of synaptic responses or persistently enhanced the number of successes in "presynaptically" silent or low-probability synapses, respectively. In double-pulses experiments, this effect was associated with a significant reduction in the paired-pulse ratio and a significant increase in the inverse squared value of the coefficient of variation of response amplitude, suggesting that long-term potentiation (LTP) expression was due to the increased probability of transmitter released. In the absence of pairing, no significant changes in synaptic efficacy could be detected. When the interval between GDPs and MF stimulation was increased, the potentiating effect progressively declined and reached the control level in less than 4 s. Mossy-fiber responses were identified on the basis of their paired-pulse facilitation, short-term frequency facilitation, and sensitivity to the group III metabotropic glutamate receptor (mGluR) agonist, 2-amino-4-phosphonobutyric acid (L-AP4). Using these criteria, we found that MFs release mainly GAB A onto CA3 pyramidal cells or GABAergic interneurons. In line with their GABAergic nature, MF responses were blocked by the GABAA receptor antagonists bicuculline or gabazine and were potentiated by NO-711, a blocker of the GABA transporter GAT-1, and by flurazepam, an allosteric modulator of GABAA receptors. In addition, chemical stimulation of granule cell dendrites with glutamate in the presence of 6,7-dinitroquinoxaline-2,3-dione (DNQX) induced into target neurons barrages of L-AP4-sensitive GABAA-mediated postsynaptic currents, further supporting the GABAergic phenotype of granule cells. As in MF, pairing GDPs with Schaffer collateral stimulation induced a persistent potentiation of spontaneous and evoked alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-mediated responses at poorly developed CA3-CA1 synapses. This effect was mediated by an increase in calcium in the postsynaptic cell via voltage-dependent calcium channels activated by the depolarizing action of GABA during GDPs. We provide evidence also that, at these connections, cyclic AMP-dependent protein kinase A (PKA) is the signaling molecule necessary for enhancing synaptic efficacy, since GDPs-induced potentiation wa

An argument is made that small-vessel stroke, which usually results in lacunar infarction, is a serious medical problem. Therefore, it is surprising that only a few animal models exist that mimic small-vessel stroke and that these models have not been used for a systematic investigation of the genesis of lacunar infarctions. We make a case that the modified pial vessel class II disruption model mimics certain important aspects of lacunar infarctions, namely cavitation caused specifically by ischemia of smaller vessels. We found evidence that upregulation of inflammatory properties within a few days of inducing lesions prevents repopulation of the lesion with reactive astrocytes. We propose that this is the key mechanism by which cavitation occurs weeks later. We also found that treatment with minocycline after induction of lesions but before cavitation prevented the formation of the fluid-filled cavity. Rather than being walled off, the lesion apparently became part of the brain parenchyma and consisted of reactive astrocytes. We conclude that this new model can be used to investigate the mechanism of lacune formation and its prevention.

In rodent hippocampal pyramidal neurons, repetitive discharges are followed by a slow afterhyperpolarization (sAHP) as a result of activation of a Ca2+-dependent K+ current. The sAHP is sensitive to activation of several G-protein coupled neurotransmitter receptors and downstream signal cascades. Modulations of the sAHP have been shown to be closely associated with synaptic plasticity, learning, and aging processes. However, it is presently unclear whether the sAHP generation is involved in hippocampal network activities. We explored this issue using an in vitro (thick-slice) model of mouse hippocampal sharp waves. Our data show that the sAHP occurs in CA3 pyramidal neurons following each sharp wave event and sAHP suppression is associated with a large increase in occurrence frequency of spontaneous sharp waves. Considering that sharp waves are important for hippocampal-cortical communication and memory processes, we postulate that the sAHP serves as an intrinsic regulatory mechanism of sharp waves and plays a significant role in hippocampus-dependent cognitive functions.

Thin acute slices and dissociated cell cultures taken from different parts of the brain have been widely used to examine the function of the nervous system, neuron-specific interactions, and neuronal development (specifically, neurobiology, neuropharmacology, and neurotoxicology studies). Here, we focus on an alternative in vitro model: brain-slice cultures in roller tubes, initially introduced by Beat Gähwiler for studies with rats, that we have recently adapted for studies of mouse cerebellum. Cultured cerebellar slices afford many of the advantages of dissociated cultures of neurons and thin acute slices. Organotypic slice cultures were established from newborn or 10-15-day-old mice. After 3-4 weeks in culture, the slices flattened to form a cell monolayer. The main types of cerebellar neurons could be identified with immunostaining techniques, while their electrophysiological properties could be easily characterized with the patch-clamp recording technique. When slices were taken from newborn mice and cultured for 3 weeks, aspects of the cerebellar development were displayed. A functional neuronal network was established despite the absence of mossy and climbing fibers, which are the two excitatory afferent projections to the cerebellum. When slices were made from 10-15-day-old mice, which are at a developmental stage when cerebellum organization is almost established, the structure and neuronal pathways were intact after 3-4 weeks in culture. These unique characteristics make organotypic slice cultures of mouse cerebellar cortex a valuable model for analyzing the consequences of gene mutations that profoundly alter neuronal function and compromise postnatal survival.