Influence of MK-801 on Brain Extracellular Calcium and Potassium Activities in Severe Hypoglycemia

Zhang, En-Tan; Hansen, Anker Jón; Wieloch, Tadeusz; Lauritzen, Martin

doi:10.1038/jcbfm.1990.18

Cited by 47 publications

(30 citation statements)

References 17 publications

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“…Conversely, changes in extracellular divalent cations may have dramatic effects on physiological neuronal function (Kuwana et al, 1998;Hsu et al, 2000). The concentrations of extracellular divalent cations have also been shown to undergo large changes in association with pathological states such as ischemia, hypoglycemia, or seizures (Harris and Symon, 1984;Somjen and Giacchino, 1985;Silver and Erecinska, 1990;Zhang et al, 1990;Kristian et al, 1993;Altura et al, 1997;Szilagyi et al, 2000). Both low Ca 2ϩ and low Mg 2ϩ can evoke seizure activity (Leschinger et al, 1993;Bikson et al, 1999;Buchheim et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium

Stout

Charles

2003

Glia

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The extracellular concentrations of Ca 2ϩ and Mg 2ϩ are well known to play important roles in the function of the central nervous system. We examined the effects of extracellular Ca 2ϩ and Mg 2ϩ on ATP release and intercellular signaling in astrocytes. [Ca 2ϩ ] o -activated whole cell currents consistent with currents through connexin hemichannels. These currents were inhibited by extracellular Mg 2ϩ . We conclude that extracellular divalent cations modulate intercellular Ca 2ϩ signaling in astrocytes by modulating the release of ATP, possibly via connexin hemichannels.

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Section: Discussionmentioning

confidence: 99%

Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium

Stout

Charles

2003

Glia

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“…The complexity of CSDs is further exempli fied by the fact that these CSDs that are evoked in the cortex by bipolar stimulation are completely blocked by MK-801 whereas only a partial effect was seen in the ischaemic penumbra in the present study. Also, under conditions of severe hypogly caemia, MK-801 was unable to block the CSDs (Zhang et al, 1990) in spite of its ability to amelio rate the hypoglycaemia-induced neuronal degener ation (Westerberg et aI., 1988). In a hypoxic hip pocampal slice preparation, Radar and Lanthorn (1989) demonstrated that persistent depolarisation could be blocked by MK-801 but not the initial de polarisation.…”

Section: Discussionmentioning

confidence: 99%

The Effect of MK-801 on Cortical Spreading Depression in the Penumbral Zone following Focal Ischaemia in the Rat

Gill

Andiné²,

Hillered

et al. 1992

J Cereb Blood Flow Metab

279

107

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Summary: Cortical spreading depression (CSD) is a tran sient depression of neuronal activity that spreads across the cortical surface. In the present studies, we have in vestigated CSD activity in the penumbral zone following permanent middle cerebral artery (MCA) occlusion in the rat (n = 16/group), using double-barreled Ca2+ -sensitive microelectrodes. Measurements of CSD activity were made for 3 h in each animal. During this time, a varying number of spontaneous CSDs were seen in the control group (total was 30, with a range of 0-7/rat). These CSDs were of varying duration: "small" (-1 min) and "big" (5-45 min) CSDs. During a CSD, the extracellular [Ca2+] decreased to 0.11 ± 0.07 mM (mean ± SD). After 3 h, the extracellular [Ca2+] in the cortex (penumbral zone) was either normal (10/16 rats) or lowered to 0.5 mM (2/16 rats) or to 0.1 mM (4/16 rats). In the caudate nucleus (isch aemic core area), all rats had an extracellular [Ca2 +] of -0.1 mM when measured after the 3 h recording period. Neuropathological evaluation of the brains of the ani mals, which had been allowed to survive for 24 h after MCA occlusion, revealed ischaemic damage in the dor solateral cortex and caudate nucleus. Administration of the noncompetitive NMDA antagonist, MK-801 (3 mglkgThe excitatory amino acid neurotransmitter L-glutamate is thought to be involved in the neuro nal degeneration that is seen following a period of cerebral ischaemia (Meldrum, 1985;Rothman and Olney, 1986;Choi, 1988 Abbreviations used: AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid; ANOV A. analysis of vari ance; CSD, cortical spreading depression; MCA, middle cerebral artery; NMDA, N-methyl-D-aspartate. 371i.p.), 30 min after MCA occlusion resulted in 24 and 29% reductions in the volume of hemispheric and cortical damage, respectively, which was highly significant (p < 0.0001); no protection was seen against caudate damage.MK-801 also significantly (p < 0.05) reduced the number of CSDs (total was IO with a range of 0-2/rat) and the degree of decrease in extracellular [Ca2+] during CSDs (low level was 0.19 ± 0.15 mM, mean ± SD). Both the number of "small CSDs" and significantly the "big CSDs" were reduced by MK-80l. The "small CSDs" were present in the border zone and also deeper within the infarct, whereas "big CSDs" and anoxic depolarisa tions only occurred closer to the infarct core. CSDs were not seen outside the border zone of the infarct. In con clusion, there was a good correlation between extracel lular [Ca2+] changes and ischaemic damage in the inf arcted region following MCA occlusion. MK-801 reduced the ischaemic damage in the penumbral zone in parallel with attentuation of the number and amplitude of CSDs and thereby a reduced intracellular Ca2 + overload. Key Words: Cerebral ischaemia-MK-801-Spreading depres sion-Glutamate-NMDA. Harreveld (1959), who showed that cortical spread ing depression (CSD) could be produced in rabbits by applying glutamate to the cortical surface and proposed that this was related to neuronal hypoxia. Further ev...

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“…The changes in ACSF ionic composition may enhance NMDAreceptor-dependent synaptic transmission, reduce calciumdependent potassium currents, and reduce short-term synaptic depression, relative to that observed with standard ACSF. The modified ACSF is, in some respects, more similar to in vivo rodent CSF than to standard ACSF (16,17). We have shown previously that experience-dependent changes in circuit excitability can be readily revealed under these ''active-slice'' conditions (10).…”

Section: Reduced Circuit Activity In L5 Pyramidal Neurons Of Mecp2-numentioning

confidence: 99%

Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett Syndrome

Dani

Chang²,

Maffei³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

570

506

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Rett Syndrome (RTT) is a devastating neurological disorder that is caused by mutations in the MECP2 gene. Mecp2-mutant mice have been used as a model system to study the disease mechanism. Our previous work has suggested that MeCP2 malfunction in neurons is the primary cause of RTT in the mouse. However, the neurophysiological consequences of MeCP2 malfunction remain obscure. Using whole-cell patch-clamp recordings in cortical slices, we show that spontaneous activity of pyramidal neurons is reduced in Mecp2-mutant mice. This decrease is not caused by a change in the intrinsic properties of the recorded neurons. Instead, the balance between cortical excitation and inhibition is shifted to favor inhibition over excitation. Moreover, analysis of the miniature excitatory postsynaptic currents (mEPSCs)͞inhibitory postsynaptic currents (mIPSCs) in the Mecp2-mutant cortex reveals a reduction in mEPSC amplitudes, without significant change in the average mIPSC amplitude or frequency. These findings provide the first detailed electrophysiological analysis of Mecp2-mutant mice and provide a framework for understanding the pathophysiology of the disease and tools for studying the underlying disease mechanisms.autism ͉ cortical circuit ͉ MeCP2 ͉ mental retardation R ett Syndrome (RTT) is a pervasive neurodevelopmental disorder associated with mental retardation, autistic behavior, and loss of previously acquired skills, including purposeful hand use and expressive language (1). Affected individuals begin to acquire motor and cognitive function normally but then regress after 6-18 months. The disease is sex-linked and is due, in most cases, to abnormal function of a single gene, the methyl CpG-binding protein MECP2 (2). Deletion of all, or the third exon, of the Mecp2 gene produces functional nulls and recapitulates, in mice, many features of the human disorder (3, 4). Mice with truncated MeCP2 also recapitulate many RTT features (5). Mecp2-null mice are normal until 5 weeks of age, when they begin to exhibit abnormal behavior resembling symptoms observed in RTT patients. Brain-specific Mecp2-mutant mice show pathological symptoms identical to those found in the germline Mecp2-null mice, thereby implicating MeCP2 malfunction in the brain as the primary cause of RTT (3). Transgenic expression of MeCP2 in postmitotic neurons in the Mecp2-mutant mice rescues the RTT phenotype (6). Overexpression of MeCP2 in postmitotic neurons in WT mice also causes behavioral and physiological abnormalities (6, 7). Taken together, these data strongly argue for the importance of MeCP2 function during the normal maturation and refinement of neural circuits, which may be compromised in Mecp2-mutant mice.Despite profound behavioral abnormalities and premature death, the neuropathological phenotype is remarkably subtle in Mecp2-mutant mice. The mutant brain weighs Ϸ20-25% less than the WT. Mutant hippocampal CA2 pyramidal neurons are Ϸ15-25% smaller than WT neurons (3). Mutant neocortical projection neurons have simplified dendritic arbors (8). Ye...

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Influence of MK-801 on Brain Extracellular Calcium and Potassium Activities in Severe Hypoglycemia

Cited by 47 publications

References 17 publications

Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium

Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium

The Effect of MK-801 on Cortical Spreading Depression in the Penumbral Zone following Focal Ischaemia in the Rat

Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett Syndrome

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