This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

https://www.cell.com/neuron/pdf/S0896-6273(01)00194-5.pdf

Activation of Synaptic NMDA Receptors Induces Membrane Insertion of New AMPA Receptors and LTP in Cultured Hippocampal Neurons

Mammalian neurons contain at least three types of excitatory amino-acid receptors, selectively activated by N-methyl-D-aspartate (NMDA) or aspartate, (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate ((S)-AMPA) and kainate. An important aspect of NMDA receptors is their regulation by a variety of factors such as glycine, Mg2+ and Zn2+ that are present in vivo. We show here that NMDA receptor responses are selectively inhibited by protons, with a 50% inhibitory concentration (IC50) that is close to physiological pH, implying that NMDA receptors are not fully active under normal conditions. (S)-AMPA and kainate responses remain unchanged at similar pH levels. Proton inhibition is voltage-insensitive and does not result either from fast channel block, a change in channel conductance, or an increase in the 50% excitatory concentration (EC50) of aspartate/NMDA or glycine. Instead, protons seem to decrease markedly the opening frequency of 30-50 pS NMDA channels, and reduce the relative proportion of longer bursts. This feature of NMDA receptors could be relevant to neurotoxic activation of NMDA receptors during ischaemia, as well as to seizure generation, as extracellular proton changes occur during both of these pathological situations. Furthermore, these results may have implications for normal NMDA receptor function as transient changes in extracellular protons occur during synaptic transmission.

Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons.

Modification of synaptic strength in the mammalian central nervous system (CNS) occurs at both pre- and postsynaptic sites. However, because postsynaptic receptors are likely to be saturated by released transmitter, an increase in the number of active postsynaptic receptors may be a more efficient way of strengthening synaptic efficacy. But there has been no evidence for a rapid recruitment of neurotransmitter receptors to the postsynaptic membrane in the CNS. Here we report that insulin causes the type A gamma-aminobutyric acid (GABA[A]) receptor, the principal receptor that mediates synaptic inhibition in the CNS, to translocate rapidly from the intracellular compartment to the plasma membrane in transfected HEK 293 cells, and that this relocation requires the beta2 subunit of the GABA(A) receptor. In CNS neurons, insulin increases the expression of GABA(A) receptors on the postsynaptic and dendritic membranes. We found that insulin increases the number of functional postsynaptic GABA(A) receptors, thereby increasing the amplitude of the GABA(A)-receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) without altering their time course. These results provide evidence for a rapid recruitment of functional receptors to the postsynaptic plasma membrane, suggesting a fundamental mechanism for the generation of synaptic plasticity.

/pdf/recruitment-of-functional-gaba-a-receptors-to-postsynaptic-3d79k0pwkd.pdf

Recruitment of functional GABA A receptors to postsynaptic domains by insulin

Calcium-induced actin depolymerization reduces NMDA channel activity

1. The whole-cell patch clamp recording technique was employed to investigate the intracellular regulation of N-methyl-D-aspartate (NMDA) receptors in cultured murine hippocampal neurones. Excitatory amino acids were repeatedly applied at regular intervals during intracellular dialysis with solutions of various composition. 2. Currents evoked by L-aspartate, an agonist of NMDA receptors, gradually 'washed out' to approximately 50% of their initial amplitude during dialysis with an intracellular solution containing CsCl and EGTA as a calcium buffer. In contrast, responses to kainate did not wash out. The wash-out of L-aspartate currents followed an exponential time course with a time constant of about 150 s. Wash-out did not appear to be related to desensitization of NMDA receptors. 3. Following wash-out, L-aspartate responses were blocked by Mg2+, ketamine or D-2-amino-5-phosphonovalerate indicating that these responses were still mediated by NMDA receptors. Furthermore, responses to NMDA itself showed wash-out to the same extent and with a time course similar to that for L-aspartate responses. 4. Neither the time course nor the extent of the wash-out of responses to L-aspartate was affected when the Ca2+ concentration of the dialysate was varied from zero to 1.5 x 10(-5) M. In addition, wash-out was unaffected by substitution of BAPTA for EGTA, indicating that wash-out was not a consequence of changes in intracellular pH related to the binding of Ca2+ to the buffer or to the kinetics of this binding. Therefore, the wash-out of NMDA currents could not be attributed to a gradual elevation of the concentration of intracellular Ca2+. 5. The extent of the wash-out of L-aspartate currents was similar for cells held at +40 versus -60 mV although the rate of wash-out was slower at the depolarized potential. In addition, the reversal potential of these currents was not altered, demonstrating that a change in driving force did not account for a component of the wash-out. 6. Inclusion of an ATP regeneration solution (Forscher & Oxford, 1985) in the dialysate prevented the wash-out of L-aspartate currents. ATP alone was less effective in preventing wash-out whereas phosphocreatine and creatine phosphokinase were ineffective by themselves. Wash-out also occurred when ATP was replaced with the non-hydrolysable analogue, beta, gamma-methyleneATP, or with GTP. In cells where wash-out of L-aspartate currents had been established, subsequent dialysis with the ATP regenerating solution partially reversed this wash-out.(ABSTRACT TRUNCATED AT 400 WORDS)

Regulation of N‐methyl‐D‐aspartate receptors revealed by intracellular dialysis of murine neurones in culture.

The objective of this study was to investigate the cellular processes involved in the formation of the cytoarchitectonics of the retina. Neurons derived from the retina, spinal cord, cerebral cortex and hippocampus were grown in dissociated monolayer tissue culture using standard techniques. The cultures of retina were unique in that the neurons actively formed into itcell clusters. On the other hand, cultures of neurons from the other regions of the CNS grew without forming any obvious histotypical pattern. Cell clusters consisted of an apparent monolayer of neurons above a population of flat cells and clusters were observed in retinal cultures derived from all species studied (mouse, cat and guinea pig). Each cluster was surrounded by whorls of fibroblasts; astrocytes (GFAP-positive cells) were often closely associated with clusters. Formation of clusters appeared to depend strongly upon the presence of cells derived from the retinal pigment epithelium (RPE) because the ability of retinal cells to form clusters was markedly impaired when the RPE was omitted from the cultures. Interestingly, monolayer cultures of neurons from other regions of the CNS could be induced to form clusters, but only when cells of the RPE layer were included at the time of plating. In cultures grown without the RPE layer, clusters did not form when media taken from cultures expressing clusters was used, indicating that the formation of clusters was not caused by a mediabourne factor. On the other hand, clusters did form when neurons without RPE were grown on feeder plates in which clusters had previously been expressed and the neurons subsequently killed by prolonged culturing or by treatment with kainic acid. Hence, physical contact between neurons and cells derived from the RPE appears critical for the formation of clusters. Our results suggest that the cellular processes underlying the formation of clusters may reflect those in the development of the retina in vivo. Thus, cluster formation may be a useful model for investigating the initial stages in the development of retinal cytoarchitecture.

Mammalian neurons in dissociated cultures form clusters in the presence of retinal pigment epithelium.

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Regulation of N‐methyl‐D‐aspartate receptors revealed by intracellular dialysis of murine neurones in culture.

Mammalian neurons in dissociated cultures form clusters in the presence of retinal pigment epithelium.