Biomedical subjects

D Büsselberg

Publications and source records attributed to D Büsselberg.

At least 19 recordsLinked to original sources

PubMed2003

A combined blockade of glycine and calcium-dependent potassium channels abolishes the respiratory rhythm.

In order to test whether glycinergic inhibition is essential for the in vivo respiratory rhythm, we analysed the discharge properties of neurones in the medullary respiratory network after blockade of glycine receptors in the in situ perfused brainstem preparation of mature wild type and oscillator mice with a deficient glycine receptor. In wild type mice, selective blockade of glycine receptors with low concentrations of strychnine (0.03-0.3 microM) provoked considerable changes in neuronal discharge characteristics: The cycle phase relationship of inspiratory, post-inspiratory and expiratory specific patterns of membrane potential changes was altered profoundly. Inspiratory, post-inspiratory and expiratory neurones developed a propensity for fast voltage oscillations that were accompanied by multiple burst discharges. These burst discharges were followed by "after-burst" hyperpolarisations that were capable of triggering secondary burst discharges. Blockade of glycine receptors and the "big" Ca2+-dependent K+-conductance by charybdotoxin (3.3 nM) resulted in loss of the respiratory rhythm, whilst only tonic discharge activity remained. In contrast, rhythmic activity was only weakened, but preserved after the "small" Ca2+-dependent activated K+ conductance was blocked with apamin (8 nM). Also low concentrations of pentobarbital sodium (6 mg/kg) abolished rhythmic respiratory activity after blockade of glycine receptors in the wild type mice and in glycine receptor deficient oscillator mice. The data imply that failure of glycine receptors provokes enhanced bursting behaviour of respiratory neurones, whilst the additional blockade of BKCa channels by charybdotoxin or with pentobarbital abolishes the respiratory rhythm.

Animals↗

PubMed2002

Histaminergic modulation of the intact respiratory network of adult mice.

Histaminergic modulation of neuronal activity in the respiratory network was investigated under normoxic and hypoxic conditions in the working heart-brainstem preparation of adult mice. Systemic application of histamine, as well as the H-1 and H-3 receptor agonists 6-[2-(4-imidazolyl)ethylamino]- N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT) and imetit, 0.5-10 micro M, significantly increased the frequency of respiratory burst discharges. Dimaprit, an H-2 receptor agonist, had no effect on respiratory activity. To test for ongoing histaminergic modulation we applied the histamine receptor antagonists pyrilamine (H-1); cimetidine (H-2) and thioperamide (H-3), each 0.5-10 micro M. Only the H-1 receptor antagonist had significant effects, viz. reduction of respiratory frequency and depression of burst amplitude. Underlying effects of histamine receptor activation were identified at the cellular level. Intracellular recordings showed that histamine mediated an increase in synaptic drive potentials in inspiratory neurones while augmentation of inhibitory and excitatory synaptic activity was observed in expiratory neurones. The augmented synaptic depolarisation of inspiratory neurones was blocked by the H-1 receptor antagonist. Histaminergic modulation is also involved in the hypoxic response of the respiratory network. Blockade of H-1 receptors significantly attenuated secondary depression of the biphasic hypoxic responses, while hypoxic augmentation was not affected. We conclude that histamine is a functional neuromodulator, which is tonically active in the respiratory network and is activated further during hypoxia. The data indicate that histaminergic neuromodulation acts predominantly via H-1 receptors.

Animals↗

PubMed2001

Reorganisation of respiratory network activity after loss of glycinergic inhibition.

gamma-Aminobutyric acid (GABA)-ergic and glycinergic inhibition is believed to play a major role in the respiratory network. In the present study we tested whether specific blockade of glycinergic inhibition resulted in changes in respiratory network interaction and function. Using the working heart-brainstem preparation from adult mice, we recorded phrenic nerve activity and the activity of different types of respiratory neurones located in the ventrolateral medulla. Strychnine (0.03-0.3 microM) was given systemically to block glycine receptors (Gly-R). During exposure to strychnine, post-inspiratory (PI) neurones shifted their onset of discharge into the inspiratory phase. As a consequence, the post-inspiratory phase failed and the rhythm changed from a three-phase cycle (inspiration, post-inspiration, expiration, with a frequency of about. 0.24 Hz) to a faster, two-phased cycle (inspiration expiration, frequency about 0.41 Hz). Inspiratory and expiratory neurones altered their augmenting membrane potential pattern to a rapidly peaking pattern. Smaller voltage oscillations at approximately 10 Hz and consisting of excitatory and inhibitory postsynaptic potential sequences occurred during the expiratory interval. Due to their high frequency and low amplitude, such oscillations would be inadequate for lung ventilation. We conclude that, under physiological conditions, glycinergic inhibition does indeed play a major role in the generation of a normal respiratory rhythm in adult mice. After failure of glycinergic inhibition a faster respiratory rhythm seems to operate through reciprocal GABAergic inhibition between inspiratory and expiratory neurones, while phase switching is organised by activation of intrinsic membrane properties.

Animals↗

PubMed2001

The respiratory rhythm in mutant oscillator mice.

Since glycinergic inhibition is important for respiratory rhythm generation in mature mammals, we tested the hypothesis that the loss of glycine receptors during postnatal development (P17-P23) of homozygous mutant oscillator mice (spd(ot)/spd(ot)) may result in serious impairment of respiratory rhythm. We measured breathing in a plethysmographic recording chamber on conscious oscillator mice and used an in situ perfused brainstem preparation to record phrenic nerve activity, as well as membrane properties of respiratory neurones. The deletion of glycinergic inhibition did not result in failure of respiratory rhythm: homozygous mutant oscillator mice continue to generate a disturbed respiratory rhythm until death. Postsynaptic activity and membrane potential trajectories of respiratory neurones revealed a persistence of GABAergic inhibition and changes in respiratory rhythm and pattern generation.

Action Potentials↗

PubMed2000

Inactivation and tachyphylaxis of heat-evoked inward currents in nociceptive primary sensory neurones of rats.

Membrane currents evoked by repeated noxious heat stimuli (43-47 degrees C) of 3 s duration were investigated in acutely dissociated dorsal root ganglion (DRG) neurones of adult rats. The heat stimuli generated by a fast solution exchanger had a rise time of 114 +/- 6 ms and a fall time of 146 +/- 13 ms. When heat stimuli were applied to heat-sensitive small (< or = 32.5 microm) DRG neurones, an inward membrane current (I(heat)) with a mean peak of 2430 +/- 550 pA was observed (n = 19). This current started to activate and deactivate with no significant latency with respect to the heat stimulus. The peak of I(heat) was reached with a rise time of 625 +/- 115 ms. When the heat stimulus was switched off I(heat) deactivated with a fall time of 263 +/- 17 ms. During constant heat stimulation I(heat) decreased with time constants of 4-5 s (inactivation). At the end of a 3 s heat stimulus the peak current was reduced by 44 +/- 5 % (n = 19). Current-voltage curves revealed outward rectifying properties of I(heat) and a reversal potential of -6.3 +/- 2.2 mV (n = 6). Inactivation was observed at all membrane potentials investigated (-80 to 60 mV); however, inactivation was more pronounced for inward currents (37 +/- 5 %) than for outward currents (23 +/- 6 %, P < 0.05). When neurones were investigated with repeated heat stimuli (3 to 5 times) of the same temperature, the peak current relative to the first I(heat) declined by 48 +/- 6 % at the 3rd stimulus (n = 19) and by 54 +/- 18 % at the 5th stimulus (n = 4; tachyphylaxis). In the absence of extracellular Ca2+ (buffered with 10 mM EGTA) inactivation (by 53 +/- 6 %) and tachyphylaxis (by 42 +/- 7 % across three stimuli) were still observed (n = 8). The same was true when intracellular Ca2+ was buffered by 10 mM BAPTA (inactivation by 49 +/- 4 %, tachyphylaxis by 52 +/- 7 % across three stimuli; n = 13). Thus, inactivation and tachyphylaxis were mainly independent of intra- and extracellular Ca2+. These results indicate that inactivation and tachyphylaxis of heat-evoked inward currents can be observed in vitro, similar to adaptation and suppression of action potential discharges elicited by comparably fast heat stimuli in vivo. Whereas the voltage dependence of I(heat) resembles that of capsaicin-induced membrane currents (I(Caps)), the independence of inactivation and tachyphylaxis of I(heat) from calcium is in clear contrast to I(Caps). A similar difference in calcium dependence of inactivation has been reported between heat-evoked and capsaicin-induced currents through the cloned capsaicin receptor channel VR1. Thus, the properties of I(heat) and of VR1 largely account for the adaptation and suppression of heat-evoked nociceptor discharges.

Animals↗

PubMed1999

Interference of lead with the calcium release activated calcium flux of osteoblast-like cells.

Lead (Pb(2+)) tends to accumulate in bone from where it is released during bone resorption, thus leading to high local concentrations of Pb(2+) with the risk of cellular toxicity. We investigated the interference of Pb(2+) with the calcium release activated calcium influx (CRAC) of osteoblast-like (OBL) cells. CRAC was elicited by depletion of intracellular Ca(2+) stores with thapsigargin and/or A23187 under Ca(2+)-free conditions and re-addition of extracellular Ca(2+). The fura-2 excitation ratio (R) was used to monitor changes of the free intracellular concentration of Ca(2+) and Pb(2+), the latter being reversible by the heavy metal chelator TPEN. Five or 12. 5 microM Pb(2+) applied simultaneously with re-added Ca(2+) reduced the immediate CRAC of OBL cells to 70% or 37% of control value, respectively. An enlarged influx of Pb(2+) occurred during CRAC, which led to a 2.7-fold faster increase of R. When 1 microM Pb(2+) was added during ongoing CRAC, the Pb(2+)-mediated increase of R correlated with the degree of CRAC (r = 0.83). Inhibitory effects of Pb(2+) on Ca(2+) ATPase activity did not contribute to the aforementioned findings. Our results demonstrated that CRAC channels of OBL cells are blocked as well as permeated by Pb(2+).

Animals↗

PubMed1999

Effects of (+/-)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats.

Kava pyrones extracted from pepper Piper methysticum are pharmacologically active compounds. Since kava pyrones exhibit anticonvulsive, analgesic and centrally muscle relaxing properties, the influence of a synthetic kava pyrone, (+/-)-kavain, on voltage-dependent ion channel currents was studied. Effects of (+/-)-kavain on voltage-activated inward currents were analysed in cultured dorsal root ganglion cells derived from neonatal rats. Voltage-activated Ca2+ and Na+ currents were elicited in the whole-cell configuration of the patch clamp technique. Extracellularly applied (+/-)-kavain dissolved in hydrous salt solutions reduced voltage-activated Ca2+ and Na+ channel currents within 3-5 min. As the solubility of (+/-)-kavain in hydrous solutions is low, dimethyl sulfoxide (DMSO) was added to the saline as a solvent for the drug in most experiments. When (+/-)-kavain was dissolved in DMSO, the drug induced a fast and pronounced reduction of both Ca2+ and Na+ currents, which partly recovered within 2-5 min even in the presence of the drug. The present study indicates that (+/-)-kavain reduces currents through voltage-activated Na+ and Ca2+ channels.

Animals↗

PubMed1999

Inhibition of rapid heat responses in nociceptive primary sensory neurons of rats by vanilloid receptor antagonists.

Recent studies demonstrated that heat-sensitive nociceptive primary sensory neurons respond to the vanilloid receptor (VR) agonist capsaicin, and the first cloned VR is a heat-sensitive ion channel. Therefore we studied to what extent heat-evoked currents in nociceptive dorsal root ganglion (DRG) neurons can be attributed to the activation of native vanilloid receptors. Heat-evoked currents were investigated in 89 neurons acutely dissociated from adult rat DRGs as models for their own terminals using the whole cell patch-clamp technique. Locally applied heated extracellular solution (effective temperature approximately 53 degrees C) rapidly activated reversible and reproducible inward currents in 80% (62/80) of small neurons (< or = 32.5 microm), but in none of nine large neurons (P < 0.001, chi(2) test). Heat and capsaicin sensitivity were significantly coexpressed in this subpopulation of small DRG neurons (P < 0.001, chi(2) test). Heat-evoked currents were accompanied by an increase of membrane conductance (320 +/- 115%; mean +/- SE, n = 7), had a reversal potential of 5 +/- 2 mV (n = 5), which did not differ from that of capsaicin-induced currents in the same neurons (4 +/- 3 mV), and were carried at least by Na(+) and Ca(2+) (pCa(2+) > pNa(+)). These observations are consistent with the opening of temperature-operated nonselective cation channels. The duration of action potentials was significantly higher in heat-sensitive (10-90% decay time: 4.45 +/- 0.39 ms, n = 12) compared with heat-insensitive neurons (2.18 +/- 0.19 ms, n = 6; P < 0.005, Student's t-test), due to an inflection in the repolarizing phase. This property as well as capsaicin sensitivity and small cell size are characteristics of nociceptive DRG neurons. When coadministered with heat stimuli, the competitive VR antagonist capsazepine (1 microM to 1 mM) significantly reduced heat-evoked currents in a dose-dependent manner (IC(50) 13 microM, Hill slope -0.58, maximum effect 75%). Preincubation for 12-15 s shifted the IC(50) by approximately 0.5 log(10) units to an estimated IC(50) of approximately 4 microM. The noncompetitive VR antagonist ruthenium red (5 microM) significantly reduced heat-evoked currents by 33 +/- 6%. The effects of both VR antagonists were rapidly reversible. Our results provide evidence for a specific activation of native VRs in nociceptive primary sensory neurons by noxious heat. The major proportion of the rapid heat-evoked currents can be attributed to the activation of these temperature-operated channels, and noxious heat may be the signal detected by VRs under physiological conditions.

Animals↗

PubMed1998

Effects of lead, mercury, and methyl mercury on gap junctions and [Ca2+]i in bone cells.

Heavy metals such as lead (Pb), mercury (Hg), and methyl mercury (MeHg) impair cell functions. For bone it is known that Pb changes bone formation rates, which depend on intracellular free calcium concentration ([Ca2+]i). Since heavy metals compete with Ca2+ at multiple sites and increased [Ca2+]i reduces gap junctional coupling between bone cells, we analyzed the effects of extracellular (e) and intracellular (i) application of Pb, Hg, and MeHg on these channels. Using primary cultures of osteoblast-like cells, relative changes of [Ca2+]i were studied in Fura-2/AM loaded cells. Parallel intracellular recordings of neighboring cells were obtained using a conventional and a patch electrode. Pb(e) (5 mumol/liter; n = 3) and Hg(e) (5 mumol/liter; n = 3) as well as Pb(i) (25 mumol/liter; n = 7) did not change the coupling (delta MP2/delta MP1). In contrast, MeHg(e) (1-10 mumol/liter; n = 6) and Hg(i) (> or = 5 mumol/liter; n = 8) reduced the coupling to 79.5 +/- 19.3% and 62.4 +/- 15.3%, respectively, within 15-20 minutes. The reduction of coupling followed individual time courses, and in no case was a steady state of decoupling reached within 20 minutes. Extracellular application of Pb(e) (5 mumol/liter, n = 74) for 20 minutes, linearly elevated the Fura emission ratio reflecting transmembrane Pb permeation rather than [Ca2+]i increase. Hg(e) (n = 48) slightly increased [Ca2+]i from 100 to < or = 200 nmol/liter, whereas MeHg(e) (5 mumol/liter, n = 52) released Ca2+ from internal stores, thus increasing [Ca2+]i up to 2 mumol/liter. In conclusion, Pb(e), Pb(i) and Hg(e) do not affect gap junctional coupling per se. Since MeHg(e) and Hg(i) deplete calcium stores, the decrease of the electric coupling is attributable to increased [Ca2+]i, which affects gap junction channels.

Animals↗

PubMed1998

A calcium release activated calcium influx in primary cultures of rat osteoblast-like cells.

Osteoblast-like (OBL) cells in primary culture were tested for their ability to generate a calcium release activated calcium flux (CRAC). Influx of Ca2+ was optically detected by fura-2. Intracellular calcium stores (ICS) were emptied in the absence of extracellular calcium ([Ca2+]e) by 5 microM thapsigargin (TG) or 2 microM A23187. Readdition of 1.8 mM [Ca2+]e increased the free intracellular Ca2+ ([Ca2+]i) after a delay of 30-60 seconds at a rate of 2.3 nM/s due to CRAC. This rate depended on [Ca2+]e and was substantially lowered if readdition of 1.8 mM [Ca2+]e was preceded by, e.g., 0.72 mM [Ca2+]e. CRAC-induced [Ca2+]i peaks were correlated (r = 0.543) with [Ca2+]i peaks during the complete depletion of ICS with A23187. Ca2+ influx due to CRAC could be blocked by flufenamic acid (100 microM) but not verapamil (20 microM). Ni2+ (1 mM), although reversibly blocking CRAC, accelerated the initial [Ca2+]i influx rate. Induction of CRAC enhanced the influx of Mn2+ 4.3-fold, as measured by quenching of fura-2 fluorescence. In summary, OBL cells exhibit a CRAC which allows for the permeation of ions other than Ca2+. This Ca2+ flux may be activated by transmembraneous gradients of Ca2+ and Ni2+.

Animals↗

PubMed1997

Coexpression of heat-evoked and capsaicin-evoked inward currents in acutely dissociated rat dorsal root ganglion neurons.

Noxious heat is able to activate heat-sensitive nociceptors in the skin very rapidly, but little is known about the mechanisms by which heat is transduced. We used the whole-cell patch-clamp technique to study the effects of noxious heat and capsaicin on freshly dissociated rat dorsal root ganglion neurons in vitro. Using temperatures between 41 degrees C and 53 degrees C, 8 of 19 small neurons (phi < or = 30 microm) exhibited a heat-evoked inward current. All heat-sensitive neurons tested were also capsaicin-sensitive. Moreover, the heat response tended to be enhanced after capsaicin (360 +/- 150 pA versus 125 +/- 45 pA, P < 0.1, n = 7). Two of five heat-insensitive neurons were excited by capsaicin; both neurons developed a heat response after capsaicin. Large neurons (phi > 30 microm) did not respond to heat (0/7), and were not sensitive to capsaicin either. These findings indicate that heat stimuli may directly activate capsaicin-sensitive primary nociceptive afferents.

Animals↗

PubMed1997

Voltage-activated calcium channel currents of rat dorsal root ganglion cells are reduced by trimethyl lead.

Using the conventional whole-cell patch-clamp recording technique with cultured neurones of rat dorsal root ganglions (DRG), we analysed the effects of trimethyl lead (TML) on voltage-activated calcium channel currents. TML reduces voltage-activated calcium channel currents in a dose-dependent manner, with a threshold concentration below 0.5 microM and a total reduction of the current ( > or =80% of the control current) at concentrations above 50 microM. Half of the current is abolished at TML concentrations between 1 and 5 microM. The action is irreversible and is not voltage dependent. After application of TML the current decreases with each activation of the channel until a steady state is reached after 8-12 min, when the channel was activated every 10 s. The channel had to be in the open state for TML to act. TML is a potent compound for reducing voltage activated calcium channel currents. These effects of TML must be taken into account in explaining the neurotoxic effects of this organic metal compound.

Animals↗

PubMed1997

Lead reduces depolarization-induced calcium entry in cultured DRG neurons without crossing the cell membrane: fura-2 measurements.

1. Cultured dorsal root ganglion of rat pups were depolarized by exposure to 50 mM K+ and the rise of [Ca2+]i was measured using fura-2 as an indicator. 2. Lead in the extracellular solution reduced the rise of [Ca2+]i in a concentration-dependent manner, with a threshold concentration of 0.25 microM. More than 80% of the calcium entry was prevented by approximately 5 microM lead. The IC50 and the Hill coefficient were 3.1 microM and 1, respectively. 3. This effect was considered to be due to a reduction of VACCCs, since applications of NMDA did not result in any rise of [Ca2+]i. 4. Since Pb2+ itself changes the fura-2 signal in a typical and characteristic manner, fura-2 is also an indicator for Pb2+. No changes in fura-2 signals were detected when lead (5 microM) was applied for several minutes in the absence of calcium, indicating that Pb2+ did not enter the cells. 5. Thus it is concluded that lead prevents calcium entry by reducing VACCCs but does not cross the cell membrane itself.

Animals↗

PubMed1997

Histaminergic system in co-cultures of hippocampus and posterior hypothalamus: a morphological and electrophysiological study in the rat.

Neurons of the tuberomammillary nucleus in the posterior hypothalamus diffusely project to most parts of the central nervous system, where their main transmitter, histamine, modulates the excitability of the target neurons. The development of a histaminergic hypothalamo-hippocampal pathway and its function were studied in organotypic co-cultures. Immunocytochemistry for histidine decarboxylase, the specific synthesizing enzyme, stained clusters of neurons in the hypothalamic tuberomammillary area. Immunolabelled varicose processes innervated the co-cultured hippocampus and established a few synaptic contacts on dendrites. Cultured tuberomammillary neurons displayed their typical membrane properties and were spontaneously active. In hippocampal pyramidal cells of the CA3 region the long-lasting afterhyperpolarization was reduced by histamine or impromidine and increased by the H2 antagonist cimetidine, but not by the H1 antagonist mepyramine. The membrane potential was depolarized in presence of an H2 agonist and hyperpolarized by an H2 antagonist. In single hippocampal cultures histamine antagonists did not affect afterhyperpolarization and membrane potential. Histaminergic neurons retain their main morphological and physiological characteristics in slice cultures and establish a functional connection with co-cultured target cells.

Animals↗

PubMed1996

Methyl mercury reduces voltage-activated currents of rat dorsal root ganglion neurons.

Methyl mercury (MeHg) is a widespread toxicant with major actions on the nervous system. Since the function of neurons depends on voltage gated ion channels, we examined the effects of micromolar concentrations of methyl mercury on voltage-activated calcium, potassium and sodium channel currents of cultured rat dorsal root ganglion (DRG) neurons. The cells, which were obtained from 2-4 day old rat pups, were whole-cell patch-clamped. Currents were separated by selective intra- and extracellular solutions as well as specific depolarizing voltage steps. We did not distinguish between different calcium, potassium or sodium channel subtypes. All three types of voltage-activated currents were irreversibly reduced by MeHg in a concentration dependent manner. Voltage-activated calcium and potassium channel currents were more sensitive to MeHg (Calcium: IC50 = 2.6 +/- 0.4 microM; Potassium: IC50 = 2.2 +/- 0.3 microM) than voltage-activated sodium channels (IC50 = 12.3 +/- 2.0 microM). The Hill coefficients for the reduction of the currents were calculated as approximately 1 for calcium and potassium channel currents and as 1.7 for sodium currents. In the cases of the voltage-activated calcium and sodium channel currents the reduction was clearly use dependent. Higher concentrations of MeHg (> or = 5 microM) resulted in a biphasic change in the holding membrane current at the potential of -80 mV in approximately 25% of the cases.

Animals↗

PubMed1996

Voltage-activated calcium channel currents of rat DRG neurons are reduced by mercuric chloride (HgCl2) and methylmercury (CH3HgCl).

The actions of bath applied mercuric chloride (HgCl2) and methylmercury (CH3HgCl) on voltage-activated calcium channel currents (VACCCs) were tested, using the whole cell patch clamp recording technique with cultured dorsal root ganglion (DRG) neurons from 2-4 day old rat pups. Both metal compounds reduced the current irreversibly in a concentration dependent fashion, reaching a new (lower) steady state within 3 to 5 min after application. Inorganic mercury was more effective in reducing the VACCCs with an IC50 of 1.3 microM, while the IC50 for methylmercury was 2.6 microM. But the threshold concentrations were below 0.25 microM for both metal compounds and the calcium channel currents were reduced by more than 90% with concentrations of 5 microM and 20 microM, respectively. The Hill coefficient for both dose-response relationship was calculated as approximately 1. Calcium channel currents were reduced over the entire voltage range, but the current-voltage relation shifted to more positive potentials in a concentration dependent manner, the effect being more pronounced with HgCl2 than with CH3HgCl (1 microM HgCl2: 10 mV shift, 5 microM CH3HgCl: 5 mV shift). At higher concentrations (> or = 2 microM for HgCl2, and > or = 10 microM for CH3HgCl) an unidentified membrane current was observed. The inorganic mercury caused an inward current, while the organic mercury compound generated a biphasic current with a transient inward and a long lasting outward component. Our results suggest that mercury compounds affect the electrical properties of neurons and thereby decrease cognitive and motor performance.

Animals↗

PubMed1995

Aluminum impairs hippocampal long-term potentiation in rats in vitro and in vivo.

Although aluminum (Al) contributes to a variety of cognitive dysfunctions and mental diseases, the underlying mechanisms of Al interactions with the nervous system are still unknown. We have studied the action of Al on synaptic transmission and long-term potentiation (LTP) by performing electrophysiological recordings both in vivo, using freely moving animals, and in vitro, using hippocampal slices. In vivo recordings of the population spikes (PSs) of dentate gyrus granule cells in response to medial perforant path stimulation were performed on both acutely and chronically (Al each day for 5 days) intraventricularly injected animals. Acute Al-infusion (calculated brain concentrations of 0.27, 0.68, and 2.7 micrograms/ml) had no influence on baseline values. Al at 0.27 microgram/ml did not alter the induction and maintenance of LTP, but 0.68 and especially 2.7 micrograms/ml Al lead to a reduction in LTP, and the potentiation declined to baseline within 2 h. In chronic animals their neuronal responsiveness was reduced and in 30% of the rats the PS was completely lost. High-frequency tetanization failed to induce LTP. In slices, field potentials were evoked stimulating Schaffer collaterals and recording pyramidal cells of the CA1 region. Bath application of 0.68 microgram/ml Al increased the baseline amplitude of the PS slightly, whereas 2.7 micrograms/ml decreased the amplitude and concentrations > 5.4 micrograms/ml blocked the PS completely. Induction of LTP in the presence of 0.68 microgram/ml Al led to a smaller increase of the PS amplitude compared to controls, but the duration of LTP was not affected. In the presence of 2.7 micrograms/ml Al LTP was further reduced and declined to baseline levels within 60 min. Given that LTP is a form of synaptic plasticity underlying some forms of learning, our data suggest that both preparations are suitable models for investigating actions of Al-induced neurotoxicity.

Aluminum↗

PubMed1995

Calcium channels as target sites of heavy metals.

Zinc (Zn), aluminium (Al), mercury (Hg), methylmercury (MeHg) and lead (Pb) extracellulary applied reduce voltage-activated calcium channel currents (VACCCs); Pb and Al also reduce N-methyl-D-aspartate (NMDA)-activated channel currents (NACCs). Pb is most effective in reducing VACCCs, with an IC50 of 0.46 microM, followed by Hg (IC50 = 1.1 microM) and MeHg (IC50 = 2.6 microM). Zn and Al were less potent (IC50 = 69 and 84 microM, respectively). Al acts on channels in the open state; its effect is pH dependent. The effects of Pb were specific for VACCCs and NACCs. Hg, Al and Zn had only minor effects on voltage-activated potassium and sodium channels, while MeHg reduced potassium channel currents (IC50 = 2.2 microM) and, at higher concentrations, sodium channel currents (IC50 = 12.3 microM). Al also reduced other receptor-activated channel currents. These results demonstrate that a variety of metal species produce different actions at the level of the cell membrane.

Aluminum↗