Biomedical subjects

J A Gorter

Publications and source records attributed to J A Gorter.

At least 37 records · Page 2Linked to original sources

PubMed1997

Global ischemia induces downregulation of Glur2 mRNA and increases AMPA receptor-mediated Ca2+ influx in hippocampal CA1 neurons of gerbil.

Transient, severe forebrain or global ischemia leads to delayed cell death of pyramidal neurons in the hippocampal CA1. The precise molecular mechanisms underlying neuronal cell death after global ischemia are as yet unknown. Glutamate receptor-mediated Ca2+ influx is thought to play a critical role in this cell death. In situ hybridization revealed that the expression of mRNA encoding GluR2 (the subunit that limits Ca2+ permeability of AMPA-type glutamate receptors) was markedly and specifically reduced in gerbil CA1 pyramidal neurons after global ischemia but before the onset of neurodegeneration. To determine whether the change in GluR2 expression is functionally significant, we examined the AMPA receptor-mediated rise in cytoplasmic free Ca2+ level ([Ca2+]i) in individual CA1 pyramidal neurons by optical imaging with the Ca2+ indicator dye fura-2 and by intracellular recording. Seventy-two hours after ischemia, CA1 neurons that retained the ability to fire action potentials exhibited a greatly enhanced AMPA-elicited rise in [Ca2+]i. Basal [Ca2+]i in these neurons was unchanged. These findings provide evidence for Ca2+ entry directly through AMPA receptors in pyramidal neurons destined to die. Downregulation of GluR2 gene expression and an increase in Ca2+ influx through AMPA receptors in response to endogenous glutamate are likely to contribute to the delayed neuronal death after global ischemia.

Animals↗

PubMed1997

The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders.

The abnormal influx of Ca2+ through glutamate receptor channels is thought to contribute to the loss of neurons associated with a number of brain disorders. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca(2+)-permeable. It is now well established that AMPA receptors exist not only in Ca(2+)-impermeable but also in Ca(2+)-permeable forms. AMPA receptors are encoded by four genes designated gluR1 (gluR-A) through gluR4 (gluR-D). The presence of the gluR2 subunit renders heteromeric AMPA receptor assemblies Ca(2+)-impermeable. Recent studies involving animal models of transient forebrain ischemia and epilepsy show that gluR2 mRNA is downregulated in vulnerable neurons. These observations suggest that downregulation of gluR2 gene expression may serve as a 'molecular switch' leading to the formation of Ca(2+)-permeable AMPA receptors and enhanced toxicity of endogenous glutamate following a neurological insult.

Animals↗

PubMed1996

The GluR2 hypothesis: Ca(++)-permeable AMPA receptors in delayed neurodegeneration.

Increased glutamate-receptor-mediated Ca++ influx is considered an important factor underlying delayed neurodegeneration following ischemia or seizures. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca(++)-permeable. It is now well established that glutamate receptors of the AMPA type, encoded by a gene family designated GluR1-GluR4, exist in both Ca(++)-permeable and Ca(++)-impermeable forms, depending on their subunit composition and degree of RNA editing. Recombinant channels assembled without GluR2 are permeable to Ca++; channels assembled with (edited) GluR2 are Ca(++)-impermeable. AMPA receptors in most adult neurons are hetero-oligomers containing GluR2 subunits, but some neurons have GluR2-less, Ca(++)-permeable receptors. The "GluR2 hypothesis" predicts that a relative reduction in the expression of GluR2 results in enhanced Ca++ influx through newly synthesized AMPA receptors, thereby increasing neurotoxicity of endogenous glutamate. Recent observations indicate reduction in GluR2 expression and predict formation of Ca(++)-permeable AMPA receptors following global ischemia and kainate-induced status epilepticus; these changes are likely to be a major factor contributing to the delayed neurodegeneration that follows these pathological events. The delayed neurodegeneration appears to be primarily apoptotic. Thus, there are at least three strategies for neuroprotection: block of formation of GluR2-less receptors, which may be possible at several levels; block of the GluR2-less receptors themselves; and block of the subsequent apoptosis.

Animals↗

PubMed1995

Modulation of N-methyl-D-aspartic acid receptors by extracellular calcium in immature and adult hippocampal slices: whole cell recordings in CA3 pyramidal cells.

Lowering extracellular calcium concentration [Ca2+]o in rat hippocampal slices can lead to an induction of epileptiform activity. It has been shown that this effect is more pronounced in slices of neonatal rats (postnatal day, PND 8-19) than in mature slices (> PND 40) and it has been suggested that unique N-methyl-D-aspartic acid (NMDA) receptor properties of immature rat hippocampal pyramidal cells contribute to this developmental effect. In a voltage clamp experiment we tested NMDA receptor properties in hippocampal pyramidal cells by measuring NMDA receptor mediated currents evoked by iontophoretic applied NMDA in the basal dendrites of CA3 pyramidal neurons. We found that lowering extracellular calcium from 2 to 1 mM, increases NMDA evoked inward current in pyramidal cells around the resting membrane potential. However, this effect is observed in slices of neonatal as well as in slices of mature rats, suggesting that there is no difference in NMDA receptor sensitivity to extracellular Ca2+ between these two age groups. The modulation of the NMDA receptor by extracellular calcium at physiological concentrations can have important consequences in pathological conditions during which extracellular calcium reaches low levels. Because this 'hypocalcemic' condition induces a larger current influx via the NMDA receptor channel at resting membrane potentials, it can further enhance cellular excitability and contribute to sustain epileptiform activity.

Age Factors↗

PubMed1995

Development of voltage-activated potassium currents in cultured cerebellar granule neurons under different growth conditions.

1. The functional expression of two potassium currents in cultured cerebellar granule cells was investigated with the whole cell patch-clamp technique in relation to development and growth condition. Cells were grown in medium containing different concentrations of potassium: 25 mM (K25) and 40 mM (K40), together referred to as "high K+"; 10 mM (K10) or "low K+"; and K10 with 100 microM N-methyl-D-aspartate (KNMDA). All conditions are known to influence maturation and survival of granule cells in culture. 2. At 2 days in vitro (DIV) the membrane capacitance, taken as index of membrane surface area, was the same for cells grown in each growth condition. At 7-9 DIV it had increased in each condition, but to a substantially larger extent in cells grown in KNMDA, K25, and K40 than in cells grown in K10. During development the input resistance only decreased in cells grown in KNMDA and high K+. 3. A delayed potassium current (IK) and a fast transient potassium current (IA) could both be recorded at 2 DIV in each growth condition, although a few neurons only expressed the IK. The IK was partially suppressed by tetraethylammonium (5 mM), whereas IA was predominantly sensitive to 4-aminopyridine (5 mM). 4. Normalized for cell capacitance, the specific IA conductance hardly changed during development in cells grown in high K+ and KNMDA. Cells in K10, however, displayed an IA with totally different properties in 23 of 24 cells; the specific IA conductance in these cells was considerably smaller at 7-9 DIV, suggesting a deletion of these channels during development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Developmental alterations in the sensitivity of hippocampal NMDA receptors to AP5.

Changes in the properties of the N-methyl-D-aspartate (NMDA) receptor are proposed as a factor in the decrease in synaptic plasticity during maturation of the brain. Alterations in the hippocampal NMDA receptor population were studied during development by comparing competitive antagonist efficacy during a window characterized by hyperexcitability and active synaptogenesis to that seen in a more mature period. A developmental change in the sensitivity of the N-methyl-D-aspartate (NMDA) evoked response to the competitive antagonist D(-)2-amino-5- phosphonopentanoic acid (D-AP5) was observed by whole-cell mode voltage-clamp, intracellular and extracellular recordings in hippocampal slices. These differences were observed in the portions of the hippocampus that contain the terminal axon arbors of the CA3 pyramidal neurons, the synaptic fields of the Schaffer collateral, associational and commissural pathways. The apparent antagonist efficacy was 2-3 times greater in immature slices obtained on postnatal day (PND) 10-16 than that observed in more mature tissue (> PND38). Given the possible role of the NMDA receptor in network plasticity, these observations could indicate a role for the molecular diversity of this important receptor subtype family in the maturation of hippocampal pathways.

2-Amino-5-phosphonovalerate↗

PubMed1994

NMDA receptor responses in adult hippocampal CA1 region after neonatal treatment with MK-801: comparison with NMDA receptor responses in the immature rat.

Neonatal MK-801 treatment from postnatal day 8-19 leads to long-term effects on brain function, suggesting that exposure to this drug leads to the development of a brain with immature network properties. One aspect of this hypothesis, that the NMDA receptors preserve their immature state after the treatment, has been tested by measuring the potency of the competitive antagonist D-AP5 in hippocampal slices. We have previously shown that an increased potency to D-AP5 is a characteristic property of NMDA receptors during early life. In the present study we measured field potentials in the CA1 region of rat hippocampal slices evoked by iontophoretic NMDA application in the Schaffer-commissural synaptic fields. Agonist dose-response curves were constructed, followed by bath applications of increasing concentrations of the antagonist D-AP5. The maximum NMDA evoked field response was the same in slices of mature control (PND70-90; 18.9 +/- 1.2 mV) and MK-801 treated rats (PND70-90; 19.3 +/- 0.9 mV), but significantly larger in immature slices (PND10-16; 24.0 +/- 0.6 mV). The sensitivity to NMDA in hippocampal slices from each group was estimated by quantifying the ionotophoretic ejection current (= dose) which evoked 50% of the maximum field response (EC50). A significantly higher sensitivity to NMDA was found in hippocampal slices obtained from MK-801-treated rats (EC50 = 3.6 +/- 0.2 nA) than in slices from control (EC50 = 6.1 +/- 0.7 nA) or immature (EC50 = 5.9 +/- 0.5 nA) animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Patterns of body temperature during feeding in rats under varying ambient temperatures.

Relationships between feeding and body temperature of rats were investigated at three ambient temperatures during the whole light/dark cycle. Basal liver temperature was negatively correlated with ambient temperature. Only at 29 degrees C liver temperature indicated activation of autonomic and locomotory thermoregulatory responses due to heat stress. At 21 degrees C, liver temperature was always higher than skin temperature. Both showed a clear circadian rhythm with higher values during the dark phase. Meal-associated temperature patterns were superimposed on this circadian rhythm. Liver and skin temperatures showed a preprandial and prandial rise. Liver temperature reached an almost similar peak value just above 39 degrees C at the end of a meal, irrespective of meal size and ambient temperatures of 13 degrees C and 21 degrees C. Liver temperature reached this peak about 2 min earlier and dropped sooner than skin temperature. These results indicate a threshold liver temperature at which feeding activity stops. The present study suggests that temperatures do not exceed this value by adaptive autonomic thermoregulatory responses shifting heat flow from core to skin and by stopping all locomotory activities including feeding, thereby avoiding deterioration of vital organs and physiological processes due to hyperthermia.

Animals↗

PubMed1992

Hippocampal kindling leads to different changes in paired-pulse depression of local evoked field potentials in CA1 area and in fascia dentata.

Monosynaptic evoked field potentials (EPs) in response to paired-pulse stimulation (20 ms interval) were recorded in area CA1 and fascia dentata of the same animal in the course of development of a kindled focus in the CA1 region. A significant reduction of paired pulse depression in response to medium and high stimulation intensity was found in CA1. A similar change was found in the fascia dentata in response to medium intensity stimulation of the angular bundle. In contrast, at high intensity, paired pulse depression was enhanced in the fascia dentata in the course of kindling. These results indicate that kindling epileptogenesis is accompanied by regionally different changes in recurrent inhibition: a reduction in CA1 and intensity dependent changes in fascia dentata.

Animals↗

PubMed1992

Chronic neonatal MK-801 treatment results in an impairment of spatial learning in the adult rat.

Chronic neonatal treatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 from postnatal day 8 through 19 has been shown to affect hippocampal NMDA receptor function of adult rats. Since many studies have shown that NMDA receptors play a crucial role in learning and memory, and since one of the hippocampal functions is spatial learning, we have examined whether this changed response of hippocampal neurons is associated with changes in its normal function. We therefore tested spatial learning and memory using a water maze in adult rats neonatally treated with MK-801. MK-801-treated rats were able to learn the spatial task as well as control rats but at a significantly slower rate. Performance in a visual cue task was not affected by the neonatal treatment, suggesting that the slower spatial learning is not caused by locomotor or sensory deficits. These results suggest that chronic NMDA receptor blockade during the neonatal period leads to long-lasting disturbances of hippocampal function.

Animals↗

PubMed1992

Chronic neonatal NMDA receptor blockade with MK-801 alters monoamine metabolism in the adult rat.

Administration of non-competitive N-methyl-D-aspartate (NMDA) antagonists in rodents leads to a characteristic motor syndrome which has been related to changes in monoamine metabolism in a variety of brain regions. We examined the question whether chronic MK-801 treatment in neonatal rats from postnatal day 8 through 19, which has been shown previously to alter NMDA receptor function, would also affect monoamine metabolism in striatum and frontal cortex of adult rats. Monoamines and their metabolites were determined 5 months after the treatment using high-performance liquid chromatography with electrochemical detection. Dihydroxyphenylacetic acid (DOPAC) concentration was elevated (greater than 40%) in both regions tested, while 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly elevated only in the cortex (19%), and 3-methoxy-4-hydroxyphenylglycol (MHPG) only in the striatum (47%). These results demonstrate that the long-lasting effects of chronic neonatal MK-801 treatment are not restricted to glutamate transmission, but include monoamine transmission as well.

Age Factors↗

PubMed1992

Hippocampal neuronal responsiveness to NMDA agonists and antagonists in the adult rat neonatally treated with MK-801.

Long-lasting effects of neonatal interference with N-methyl-D-aspartate (NMDA) receptors were investigated by measuring responses to micro-iontophoretically applied NMDA agonists/antagonist in hippocampal neurons of the adult rat. Rat pups were chronically treated with MK-801 from postnatal day 8 through 19 and tested at postnatal day 70-100. CA1 cell responses to glutamate were not affected by the neonatal treatment. However, a stronger suppression of the NMDA evoked response by the NMDA site antagonist amino-5-phosphonovalerate (APV) was measured, suggesting a long-lasting configurational change of the NMDA receptor. The NMDA evoked responses were equally strong suppressed by MK-801 in both groups, suggesting that channel sites were not affected by this treatment.

2-Amino-5-phosphonovalerate↗

PubMed1991

Spectral analysis of the electroencephalogram in neonatal rats chronically treated with the NMDA antagonist MK-801.

In order to study the involvement of NMDA-receptor activation in brain development, rat pups were chronically treated with the non-competitive NMDA antagonist MK-801 during the neonatal period. We recorded the cortical EEG at various vigilance states throughout the treatment period. Spectral analysis of the EEG showed reduced power in the delta (delta) frequency range (1.5-4 Hz) during quiet sleep and less power in the theta (theta) range (4-7 Hz) during REM-sleep in MK-801 animals than in controls. No significant differences were found for the total time spent in each of the different vigilance states. We conclude that chronic MK-801 treatment probably causes a developmental retardation in state-related brain activities.

Animals↗

PubMed1991

Chronic neonatal MK-801 administration leads to a long-lasting increase in seizure sensitivity during the early stages of hippocampal kindling.

Persistent effects of chronic neonatal administration of the N-methyl-D-aspartate (NMDA) antagonist MK-801 were investigated by measuring susceptibility to CA1 kindling epileptogenesis in adulthood. Rat pups were chronically treated with MK-801 from postnatal day 8 through day 19. Hippocampal kindling showed an increase in electrical seizure duration in the MK-801-treated group as compared with controls along with a more severe expression of behavioral seizures during the first few kindling stimulations. These results show that neonatal interference with NMDA receptor function leads to a long-lasting increase in hippocampal excitability.

Animals↗

PubMed1991

A long-lasting decrease in the inhibitory effect of GABA on glutamate responses of hippocampal pyramidal neurons induced by kindling epileptogenesis.

Experiments were carried out to test whether changes in the sensitivity of hippocampal pyramidal neurons to the neurotransmitters glutamate, GABA and noradrenaline may be associated with the establishment of an epileptogenic focus induced by kindling. The effects of iontophoretically applied neurotransmitters on the firing rate of single units were quantified in the rat hippocampal CA1 area in kindled and control animals. Kindling was induced by electrical tetanic stimulation of the Schaffer collateral/commissural fibers. Firing was evoked by local glutamate iontophoresis while simultaneous GABA or noradrenaline application suppressed this response. A significant reduction of the GABAergic inhibitory action on the firing rate in kindled animals studied around four or around 42 days after the last convulsion was found. In the same neurons, the suppressive effect of noradrenaline was not different from controls. The neurons of kindled animals, investigated around four days after the last seizure, had a reduced sensitivity for glutamate; more glutamate ejection current was needed to evoke firing or to evoke the maximum firing rate. In contrast, the responsiveness for glutamate was significantly increased long-term after the last convulsion. These findings demonstrate that hippocampal Schaffer collateral kindling is associated with a long-lasting reduced effectiveness of the GABA-mediated response on glutamate-evoked firing in CA1.

Analysis of Variance↗

PubMed1990

Neonatal clonidine treatment results in long-lasting changes in noradrenaline sensitivity and kindling epileptogenesis.

In the present experiment we tested the hypothesis that early interference with noradrenaline transmission can have permanent consequences for brain function in adulthood. Neonatal depletion of noradrenaline by daily subcutaneous injections of clonidine results in supersensitivity to noradrenaline in adult hippocampal CA1 cells as shown in our previous microiontophoretic study. These findings were confirmed and extended here with dose-response curves. Furthermore, we tested whether this form of neonatal interference with noradrenaline also permanently affects long-lasting plasticity as revealed in kindling epileptogenesis in adulthood. The initiation of the epileptic activity after the kindling stimulation was significantly delayed in the clonidine-treated group, and all measured parameters of seizure expression tended to be retarded in comparison with saline-treated control rats. This indicates that noradrenaline supersensitivity induced by neonatal clonidine treatment retards kindling development in adulthood.

Animals↗

PubMed1990

Cortical neuron sensitivity to neurotransmitters following neonatal noradrenaline depletion.

In order to test the functional significance of rapid eye movement (REM)-sleep and noradrenergic activity for cerebral cortex maturation, rat pups were daily injected with clonidine from 8 to 21 days of life. Previous studies have shown that this treatment reduces the amount of time spent in REM-sleep and the level of noradrenaline turnover in the brain. For long-term consequences of such treatment in adulthood, cortical neuron responses to micro-iontophoretically applied neurotransmitters were studied. No significant differences were found in the single cell responses to glutamate, GABA or noradrenaline in the cerebral cortex of clonidine treated rats as compared with age matched controls. However, the magnitude of GABAergic depression of glutamate induced neuronal responses was greater in the clonidine than in the control group.

Animals↗

PubMed1990

Lasting effects of early noradrenergic receptor occupation on brain noradrenaline turnover and on beta-receptors.

Neuroactive substances reaching the developing brain can affect the formation of the functionality of nervous circuitry. To explain this so-called functional neuroteratology it has been proposed that neurotransmission has persistently been altered. Pharmacological interference with the developing central noradrenergic system in the rat by means of drugs like clonidine, yohimbine and propranolol, indeed revealed lasting changes in the turnover of noradrenaline in several brain areas, but no changes were found in beta-receptor density. It is assumed that either alpha-receptor density is affected or that signal transduction is altered, since electrophysiologically a persistent supersensitivity was found for the noradrenaline-evoked depression of glutamate-evoked firing in e.g. CA1 pyramidal cells of the hippocampus. Elucidation of the underlying neurochemical mechanisms of such lasting effects of perinatal exposure to noradrenergic drugs aims at establishing the role of noradrenaline in development, but also to provide physicians with the possibility to better assess the advantages and disadvantages of drugs to be prescribed during reproduction and, hence, to make the best choice of treatment.

Animals↗