Biomedical subjects

H Z Yin

Publications and source records attributed to H Z Yin.

At least 19 recordsLinked to original sources

PubMed2000

AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro.

The reason for the selective vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS) is primarily unknown. A possible factor is the expression by motor neurons of Ca(2+)-permeable AMPA/kainate channels, which may permit rapid Ca(2+) influx in response to synaptic receptor activation. However, other subpopulations of central neurons, most notably forebrain GABAergic interneurons, consistently express large numbers of these channels but do not degenerate in ALS. Indeed, when subjected to identical excitotoxic exposures, motor neurons were more susceptible than GABAergic neurons to AMPA/kainate receptor-mediated neurotoxicity. Microfluorimetric studies were performed to examine the basis for the difference in vulnerability. First, AMPA or kainate exposures appeared to trigger substantial mitochondrial Ca(2+) loading in motor neurons, as indicated by a sharp increase in intracellular Ca(2+) after addition of the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenyl hydrazone (FCCP) after the agonist exposure. The same exposures caused little mitochondrial Ca(2+) accumulation in GABAergic cortical neurons. Subsequent experiments examined other measures of mitochondrial function to compare sequelae of AMPA/kainate receptor activation between these populations. Brief exposure to either AMPA or kainate caused mitochondrial depolarization, assessed using tetramethylrhodamine ethylester, and reactive oxygen species (ROS) generation, assessed using hydroethidine, in motor neurons. However, these effects were only seen in the GABAergic neurons after exposure to the nondesensitizing AMPA receptor agonist kainate. Finally, addition of either antioxidants or toxins (FCCP or CN(-)) that block mitochondrial Ca(2+) uptake attenuated AMPA/kainate receptor-mediated motor neuron injury, suggesting that the mitochondrial Ca(2+) uptake and consequent ROS generation are central to the injury process.

Buffers↗

PubMed2000

AMPA/kainate receptor-triggered Zn2+ entry into cortical neurons induces mitochondrial Zn2+ uptake and persistent mitochondrial dysfunction.

Rapid Zn2+ influx through Ca2+-permeable AMPA/kainate (Ca-A/K) channels triggers reactive oxygen species (ROS) generation and is potently neurotoxic. The first aim of this study was to determine whether these effects might result from direct mitochondrial Zn2+ uptake. Adapting the mitochondrially sequestered divalent cation sensitive probe, rhod-2, to visualize mitochondrial Zn2+, present studies indicate that Zn2+ is taken up into these organelles. The specificity of the signal for Zn2+ was indicated by its reversal by Zn2+ chelation, and its mitochondrial origin indicated by its speckled extranuclear appearance and by its elimination upon pretreatment with the mitochondrial protonophore, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP). Consistent with inhibition of mitochondrial Zn2+ uptake, FCCP also slowed the recovery of cytosolic Zn2+ elevations in Ca-A/K(+) neurons. Further studies sought clues to the high toxic potency of intracellular Zn2+. In experiments using the mitochondrial membrane polarization (DeltaPsi(m))-sensitive probe tetramethylrhodamine ethyl ester and the ROS-sensitive probe hydroethidine, brief kainate exposures in the presence of 300 microM Zn2+ (with or without Ca2+) resulted in prolonged loss of DeltaPsi(m) and corresponding prolonged ROS generation in Ca-A/K(+) neurons, in comparison to the more rapid recovery from loss of DeltaPsi(m) and transient ROS generation after kainate/1.8 mM Ca2+ exposures.

Animals↗

PubMed1999

Dendritic localization of Ca(2+)-permeable AMPA/kainate channels in hippocampal pyramidal neurons.

Although it is well established that cortical and hippocampal gamma-aminobutyric acid (GABA)-ergic neurons generally have large numbers of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate channels (Ca-A/K channels), their presence on pyramidal neurons is controversial. Ca2+ permeability of AMPA channels is regulated by expression of a particular glutamate receptor subunit (GluR2), which confers Ca2+ impermeability to heteromeric channels. Most electrophysiology studies, as well as in situ hybridization and immunolabeling studies demonstrating expression of GluR2 mRNA or peptide in pyramidal neurons, have provided evidence against the presence of Ca-A/K channels on pyramidal neurons. However, observations that pyramidal neurons often appear to be labeled by kainate-stimulated Co2+ influx (Co2+(+) cells), a histochemical stain that identifies cells possessing Ca-A/K channels, suggests that they may have these channels. The present study futher examines cellular and subcellular distribution of Ca-A/K channels on hippocampal pyramidal neurons in slice as well as in culture. To this end, techniques of kainate-stimulated Co2+ influx labeling, supplemented by AMPA receptor subunit immunocytochemistry and fluorescent imaging of kainate-stimulated intracellular Ca2+ ([Ca2+]i) rises are employed. Co2+ labeling is often seen in pyramidal neuronal dendrites in both slice and in culture. In addition, although GluR1 and 4 staining in these neurons is often seen in the soma and dendrites, GluR2 label, when evident, is generally more restricted to the soma. Finally, measurement of kainate-stimulated [Ca2+]i rises in cultured neurons, assessed by using low affinity Ca2+ indicators in the presence of N-methyl-D-aspartate (NMDA) receptor and voltage-sensitive Ca2+ channel blockade, often shows dendritic rises to precede those in the somata. Thus, these data support the hypothesis that Ca-A/K channels are present in dendritic domains of many pyramidal neurons, and may help to provide resolution of the apparently conflicting data regarding their distribution.

Animals↗

PubMed1999

Glutamate triggers preferential Zn2+ flux through Ca2+ permeable AMPA channels and consequent ROS production.

ZN2+ co-released with glutamate at excitatory synaptic sites can enter and cause injury to postsynaptic neurons. While prior studies using the slowly desensitizing agonist kainate suggested preferential Zn2+ permeation through Ca2+ permeable AMPA/kainate (Ca-A/K) channels, the present study aims to assess relevance of those findings upon more physiological receptor activation. Microfluorimetric techniques were used to measure [Zn2+]i attained upon exposure to the rapidly desensitizing agonist AMPA or to the physiological agonist glutamate, in the presence of 300 microM Zn2+. Under these conditions, micromolar [Zn2+]i rises (delta[Zn2+]i) were still observed to occur selectively in the subset of neurons that express large numbers of Ca-A/ K channels. Further studies using the oxidation sensitive dye, hydroethidine, revealed Zn2+-dependent reactive oxygen species generation that paralleled delta[Zn2+]i, with rapid oxidation only observed in the case of Zn2+ entry through Ca-A/K channels.

Animals↗

PubMed1999

Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production.

Synaptically released Zn2+ can enter and cause injury to postsynaptic neurons. Microfluorimetric studies using the Zn2+-sensitive probe, Newport green, examined levels of [Zn2+]i attained in cultured cortical neurons on exposure to N-methyl-D-asparte, kainate, or high K+ (to activate voltage-sensitive Ca2+ channels) in the presence of 300 microM Zn2+. Indicating particularly high permeability through Ca2+-permeable alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionic-acid/kainate (Ca-A/K) channels, micromolar [Zn2+]i rises were observed only after kainate exposures and only in neurons expressing these channels [Ca-A/K(+) neurons]. Further studies using the oxidation-sensitive dye, hydroethidine, revealed Zn2+-dependent reactive oxygen species (ROS) generation that paralleled the [Zn2+]i rises, with rapid oxidation observed only in the case of Zn2+ entry through Ca-A/K channels. Indicating a mitochondrial source of this ROS generation, hydroethidine oxidation was inhibited by the mitochondrial electron transport blocker, rotenone. Additional evidence for a direct interaction between Zn2+ and mitochondria was provided by the observation that the Zn2+ entry through Ca-A/K channels triggered rapid mitochondrial depolarization, as assessed by using the potential-sensitive dye tetramethylrhodamine ethylester. Whereas Ca2+ influx through Ca-A/K channels also triggers ROS production, the [Zn2+]i rises and subsequent ROS production are of more prolonged duration.

Calcium↗

PubMed1999

Prostate specific antigen is detectable in formalin-fixed semen.

OBJECTIVE: To conduct a pilot study to test whether or not prostate specific antigen (PSA) and/or PSA-positive cells can be detected and characterized in semen specimens archived in aldehyde fixative. MATERIALS AND METHODS: Specimens from 12 men were examined, six before elective vasectomy and six undergoing infertility evaluation. Fixed semen elements were assessed immunocytologically using monoclonal antibodies against PSA and leucocyte common antigen, CD 45, as a control. RESULTS: PSA was detectable in the semen from the fertile men as amorphous protein and contained within round vesicles (prostasomes). Semen from men undergoing infertility evaluation contained a greater variation in detectable forms and amount of PSA than the specimens from the fertile men, including PSA associated with some nonspermatozoal cells (NSCs). CONCLUSION: PSA is detectable by immunocytological analysis of semen specimens archived in aldehyde-based fixative. Three forms of PSA were detected; within round vesicles characteristic of prostasomes, associated with some NSCs, and as amorphous protein. The detected variations suggest that analysis of PSA-positive semen elements may provide important insights into prostate physiology.

Fixatives↗

PubMed1999

Human sperm cryobanking. Use of modified liquid nitrogen vapor.

OBJECTIVE: To study a modified liquid nitrogen vapor cryopreservation technique for human spermatozoa. STUDY DESIGN: The freezing rate of the modified liquid nitrogen vapor method was controlled using thermocouple probes to simultaneously measure the temperature of both the liquid nitrogen vapor and semen specimen. Sperm cryosurvival and postthaw velocity were compared using a programmable biologic freezer and our modified vapor freezing procedure. RESULTS: There were no significant differences in postthaw sperm viability between the two methods. CONCLUSION: This modified vapor freezing technique permits controlled cooling that is efficient, rapid and inexpensive.

Cryopreservation↗

PubMed1998

Rapid Ca2+ entry through Ca2+-permeable AMPA/Kainate channels triggers marked intracellular Ca2+ rises and consequent oxygen radical production.

The widespread neuronal injury that results after brief activation of highly Ca2+-permeable NMDA channels may, in large part, reflect mitochondrial Ca2+ overload and the consequent production of injurious oxygen radicals. In contrast, AMPA/kainate receptor activation generally causes slower toxicity, and most studies have not found evidence of comparable oxygen radical production. Subsets of central neurons, composed mainly of GABAergic inhibitory interneurons, express AMPA/kainate channels that are directly permeable to Ca2+ ions. Microfluorometric techniques were performed by using the oxidation-sensitive dye hydroethidine (HEt) to determine whether the relatively rapid Ca2+ flux through AMPA/kainate channels expressed on GABAergic neurons results in oxygen radical production comparable to that triggered by NMDA. Consistent with previous studies, NMDA exposures triggered increases in fluorescence in most cultured cortical neurons, whereas high K+ (50 mM) exposures (causing depolarization-induced Ca2+ influx through voltage-sensitive Ca2+ channels) caused little fluorescence change. In contrast, kainate exposure caused fluorescence increases in a distinct subpopulation of neurons; immunostaining for glutamate decarboxylase revealed the responding neurons to constitute mainly the GABAergic population. The effect of NMDA, kainate, and high K+ exposures on oxygen radical production paralleled the effect of these exposures on intracellular Ca2+ levels when they were monitored with the low-affinity Ca2+-sensitive dye fura-2FF, but not with the high-affinity dye fura-2. Inhibition of mitochondrial electron transport with CN- or rotenone almost completely blocked kainate-triggered oxygen radical production. Furthermore, antioxidants attenuated neuronal injury resulting from brief exposures of NMDA or kainate. Thus, as with NMDA receptor activation, rapid Ca2+ influx through Ca2+-permeable AMPA/kainate channels also may result in mitochondrial Ca2+ overload and consequent injurious oxygen radical production.

Animals↗

PubMed1998

Kainate-stimulated Zn2+ uptake labels cortical neurons with Ca2+-permeable AMPA/kainate channels.

The endogenous cation, Zn2+, is synaptically released and may trigger neurodegeneration after permeating through NMDA channels, voltage sensitive Ca2+ channels (VSCC), or Ca2+ permeable AMPA/kainate channels (Ca-A/K). Neurons expressing Ca-A/K can be identified by a histochemical stain based upon kainate-stimulated Co2+ uptake (Co2+(+) neurons). The primary objective of this study was to determine whether a similar approach could be employed to visualize agonist-stimulated intracellular Zn2+ accumulation, and, thus, to test the hypothesis that Ca-A/K permit particularly rapid Zn2+ flux. Substituting Zn2+ for Co2+ during agonist-stimulated uptake, followed by Timm's sulfide-silver staining to visualize intracellular Zn2+, resulted in distinct labeling of a subpopulation of cortical neurons (Zn2+(+) neurons) closely resembling Co2+(+) neurons, suggesting that, like Co2+, Zn2+ may permeate Ca-A/K with particular rapidity. Neither NMDA nor high K+ triggered comparable Zn2+ accumulation, indicating substantially greater permeation through Ca-A/K than through NMDA channels or VSCC. Both fluorescence studies of intracellular Zn2+ accumulation and double staining studies (using SMI-32 and anti-glutamate decarboxylase antibodies, both markers of cortical neuronal subsets), support the contention that Zn2+ and Co2+ labeling identify a common set of neurons characterized by expression of AMPA/kainate channels directly permeable to Zn2+ and Co2+ as well as Ca2+. Furthermore, the preferential destruction of Zn2+(+) neurons (like Co2+(+) neurons) after brief kainate exposures in the presence of lower, more physiologic concentrations of Zn2+ suggests that Zn2+ permeation through Ca-A/K could contribute to selective neurodegeneration in disease. Finally, the study provides a novel and potentially advantageous histochemical approach for kainate-stimulated Co2+ or Zn2+ uptake labeling, using a room temperature technique (Timm's staining) rather than the usual hot AgNO3 development of the Co2+ stain.

Animals↗

PubMed1996

Ca(2+)-permeable AMPA/kainate and NMDA channels: high rate of Ca2+ influx underlies potent induction of injury.

Neurodegeneration may occur secondary to glutamate-triggered Ca2+ influx through any of three routes: NMDA channels, voltage-sensitive Ca2+ channels (VSCC), and Ca(2+)-permeable AMPA/kainate channels (Ca-A/K). This study aims to examine Ca2+ ion dynamics in the generation of excitotoxic injury by correlating the relative amounts of 45Ca2+ that flow into cortical neurons through each of these routes over a 10 min epoch ("10 min Ca2+ loads;" a measure of influx rate), with resultant levels of intracellular free Ca2+ ([Ca2+]) and subsequent injury. Neurons possessing Ca-A/K make up a small subset (approximately 13%) of cortical neurons in culture, which can be identified by a histochemical stain based on kainate-stimulated Co2+ uptake (Co2+ (+) neurons) and which are unusually vulnerable to AMPA/kainate receptor-mediated injury. Initial studies using brief kainate exposures (to selectively destroy Co2+ (+) neurons) along with kainate-triggered 45Ca2+ influx measurements suggested that kainate causes rapid Ca2+ influx into Co2+ (+) neurons (comparable to that caused by NMDA). Influx through both Ca-A/K and NMDA channels increased proportionately with extracellular Ca2+, suggesting that these channels have high Ca2+ permeability. When cultures were subjected to exposures that gave similar 10 min Ca2+ loads through different routes, comparable levels of injury were observed, suggesting that net intracellular Ca2+ accumulation is a critical determinant of injury. However, the relationship between [Ca2+]i and influx was less direct: although exposures that gave the lowest or highest 10 min Ca2+ loads showed correspondingly lower or higher mean [Ca2+]i responses, there appears to be a wide range of exposures over which individual neuronal differences and sequestration/buffering mechanisms obscure [Ca2+]i as a reflection of influx rate.

Animals↗

PubMed1996

Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro.

The nonphosphorylated neurofilament marker SMI-32 stains motor neurons in spinal cord slices and stains a subset of cultured spinal neurons ["large SMI-32(+) neurons"], which have a morphology consistent with motor neurons identified in vitro: large cell body, long axon, and extensive dendritic arborization. They are found preferentially in ventral spinal cord cultures, providing further evidence that large SMI-32(+) neurons are indeed motor neurons, and SMI-32 staining often colocalizes with established motor neuron markers (including acetylcholine, calcitonin gene-related peptide, and peripherin). Additionally, choline acetyltransferase activity (a frequently used index of the motor neuron population) and peripherin(+) neurons share with large SMI-32(+) neurons an unusual vulnerability to AMPA/kainate receptor-mediated injury. Kainate-induced loss of these motor neuron markers is Ca2+-dependent, which supports a critical role of Ca2+ ions in this injury. Raising extracellular Ca2+ exacerbates injury, whereas removal of extracellular Ca2+ is protective. A basis for this vulnerability is provided by the observation that most peripherin(+) neurons, like large SMI-32(+) neurons, are subject to kainate-stimulated Co2+ uptake, a histochemical stain that identifies neurons possessing Ca2+-permeable AMPA/kainate receptor-gated channels. Finally, of possibly greater relevance to the slow motor neuronal degeneration in diseases, both large SMI-32(+) neurons and peripherin(+) neurons are selectively damaged by prolonged (24 hr) low-level exposures to kainate (10 microM) or to the glutamate reuptake blocker L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM). During these low-level kainate exposures, large SMI-32(+) neurons showed higher intracellular Ca2+ concentrations than most spinal neurons, suggesting that Ca2+ ions are also important in this more slowly evolving injury.

Animals↗

PubMed1995

Zn(2+) permeates Ca(2+) permeable AMPA/kainate channels and triggers selective neural injury.

Brief exposures of cortical cultures to kainate (100 mu M) plus Zn(2+) (300 mu M) cause fluorescence of the Zn(2+) sensitive dye, TS-Q, to appear in virtually all neurons, probably reflecting depolarization and secondary Zn(2+) permeation through voltage-sensitive Ca(2+) channels. However, if Na+ ions are removed from the media (to prevent depolarization), prominent TS-Q fluorescence is still observed in the small subset of neurons labeled by kainate stimulated Co(2+) uptake (Co(2+)(+) neurons), a histochemical technique that identifies neurons expressing Ca(2+) permeable AMPA/kainate receptor-gated channels. Kainate/Zn(2+) exposures in Na+ containing media with lower (50-100 mu M) Zn(2+) concentrations resulted 24 h later in selective loss of the Co(2+)(+) neurons, suggesting that these channels may permit particularly high rates of Zn(2+) passage. Thus, direct permeation of synaptically released Zn(2+) through Ca(2+) permeable AMPA/kainate channels could contribute to selective degeneration of neurons in disease as well as subserving physiological signaling functions.

Animals↗

PubMed1995

Spinal cord neurons are vulnerable to rapidly triggered kainate neurotoxicity in vitro.

Initial studies found glutamate injury to murine spinal cultures (14-17 days in vitro) to reflect contributions of both NMDA and AMPA/kainate receptors. Subsequent experiments found the spinal cultures to be more sensitive than cortical cultures to injury from prolonged low level kainate exposures, and, unlike cortical cultures, to be significantly damaged by relatively brief (30-60 min) kainate exposures. This rapidly triggered kainate damage to spinal neurons is Ca(2+)-dependent. Also, more than 40% of spinal neurons (in comparison to about 15% of cortical neurons) are subject to kainate-activated Co2+ uptake (Co2+(+) neurons), a histochemical technique that labels neurons with Ca(2+)-permeable AMPA/kainate channels. These spinal Co2+(+) neurons are very sensitive to Ca(2+)-dependent kainate injury, and show greater kainate-induced elevations in intracellular Ca2+ concentrations ([Ca2+]i) than other spinal neurons during low level kainate exposures. Thus, the heightened vulnerability of spinal neurons to kainate toxicity may at least in part reflect the large proportion that possess Ca2+ permeable AMPA/kainate channels, permitting receptor activation to trigger rapid Ca2+ influx and overwhelm the cells Ca2+ homeostatic capabilities.

Animals↗

PubMed1995

Ca2+ permeable AMPA/kainate channels permit rapid injurious Ca2+ entry.

Small subsets of central neurons possessing Ca2+ permeable AMPA/kainate channels can be identified by a histochemical stain based on kainate-stimulated Co2+ uptake (Co2+(+)neurons) and are unusually vulnerable to AMPA/kainate receptor-mediated injury. Using brief kainate exposures (which selectively destroy Co2+(+) neurons) along with kainate triggered 45Ca2+ influx measurements, we estimate kainate to cause an unusually high rate of Ca2+ influx into Co2+(+) neurons. Also, while fura-2 Ca2+ imaging revealed low (10 microM) kainate exposures to preferentially induce intracellular free Ca2+ ([Ca2+]i) elevations in Co2+(+) neurons, intense (100 microM) kainate exposures used in the 45Ca2+ influx studies triggered comparable [Ca2+]i rises in all neurons. These findings suggest that the exceptional vulnerability of Co2+(+) neurons to AMPA/kainate receptor-mediated injury reflects a high rate of agonist triggered Ca2+ influx, and that [Ca2+]i rises may only poorly reflect influx rate.

Animals↗

PubMed1995

In vitro kainate injury to large, SMI-32(+) spinal neurons is Ca2+ dependent.

The non-phosphorylated neurofilament marker, SMI-32, identifies ventral horn motor neurons in spinal cord slice. We show here that SMI-32 marks a subset of spinal cord neurons in culture. Many of these neurons ('large SMI-32(+) neurons') have morphological characteristics of identified motor neurons in vitro: large cell body size (> 20 microns), extensive neuritic arborization and, generally, one particularly long process. These neurons are preferentially injured by brief (40 min) kainate exposures, but not by NMDA exposures. This rapidly triggered damage to large SMI-32(+) neurons is Ca2+ dependent. In addition, most of the SMI-32(+) neurons exhibit kainate-stimulated Co2+ uptake, a histochemical technique which marks neurons possessing Ca(2+)-permeable AMPA/kainate receptor-gated channels. The unusual vulnerability of large SMI-32(+) spinal neurons to kainate toxicity may result from rapid Ca2+ entry through Ca(2+)-permeable AMPA/kainate channels.

Animals↗

PubMed1995

Ca2+ and in vitro kainate damage to cortical and hippocampal SMI-32(+) neurons.

SMI-32 is a monoclonal antibody to non-phosphorylated neurofilament epitopes, which labels subsets of pyramidal neurons prone to degeneration in Alzheimer's disease. We found SMI-32 to identify a small minority of neurons in dissociated cultures of murine cortex and hippocampus (SMI-32(+) neurons). Labeled neurons, which were larger than average and were often immunoreactive for GABA, were preferentially destroyed by brief kainate exposures. This rapidly triggered kainate damage to SMI-32(+) neurons was dependent upon the presence of Ca2+ in the media during the toxic exposure. Furthermore, most SMI-32(+) neurons in both cortex and hippocampus were subject to kainate-activated cobalt uptake, a histochemical procedure that marks cells with Ca2+ permeable AMPA/kainate channels. The unusual vulnerability of cortical and hippocampal SMI-32(+) neurons to AMPA/kainate receptor-mediated injury may result from rapid Ca2+ entry through Ca2+ permeable AMPA/kainate receptor-gated channels.

Animals↗

PubMed1995

Semen leukocytes: friends or foes?

OBJECTIVE: To test the hypothesis that male reproductive tract leukocytes function in the elimination of abnormal spermatozoa from ejaculated semen. DESIGN: Semen specimens with > or = 2 x 10(6) nonspermatozoal cells/mL were examined for leukocytes and for mature sperm with ideal morphology. SETTING: Andrology laboratory of a Center of Assisted Reproductive Technology. RESULTS: Semen specimens with elevated concentrations of leukocytes contained a significantly higher frequency of sperm with ideal morphology than semen specimens with elevated numbers of immature germ cells and low numbers of leukocytes. CONCLUSIONS: The direct correlation between leukocyte density and sperm with ideal morphology supports the concept that sperm surveillance is a normal function of male reproductive tract leukocytes. Understanding such germ cell-leukocyte interactions may provide valuable new insights into immunologic control mechanisms in male reproductive tract tissues.

Adult↗

PubMed1994

Kainate injury to cultured basal forebrain cholinergic neurons is Ca2+ dependent.

WHILE exposure times of several hours or more are needed for kainate to induce widespread degeneration of most cortical or basal forebrain neurons, basal forebrain cholinergic neurons, as identified by choline acetyltransferase immunocytochemistry, were substantially damaged by brief (45 min) kainate exposures. This rapidly triggered damage to basal forebrain cholinergic neurons is Ca2+ dependent. Also, basal forebrain cholinergic neurons have unusually large elevations in intracellular Ca2+ concentration in response to kainate, and generally exhibit kainate-activated Co2+ uptake, suggesting that they possess Ca(2+)-permeable AMPA/kainate receptor-gated channels. The heightened vulnerability of basal forebrain cholinergic neurons to kainate toxicity may reflect rapid Ca2+ entry through Ca(2+)-permeable AMPA/kainate channels.

Animals↗