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PubMed1996

Timing of neuronal death in trkA, trkB and trkC mutant embryos reveals developmental changes in sensory neuron dependence on Trk signalling.

The sensory neurons of the embryonic mouse trigeminal ganglion are supported in culture by different neurotrophins at successive stages of development. Initially the neurons survive in response to BDNF and NT3 and later switch to becoming NGF-dependent (Buchman, V. I. and Davies, A. M. (1993), Development 118, 989-1001). To determine if this in vitro switch in neurotrophin responsiveness is physiologically relevant, we studied the timing of neuronal death in the trigeminal ganglia of embryos that are homozygous for null mutations in the trkA, trkB and trkC genes, which encode receptor tyrosine kinases for NGF, BDNF and NT3, respectively. In wild-type embryos, the number of pyknotic nuclei increased from E11 to peak between E13 and E14, and decreased gradually at later ages, becoming negligible by birth. Neuronal death in the trigeminal ganglia of trkA-/- embryos also peaked between E13 and E14, but was almost threefold greater than in wild-type embryos at this stage. Whereas there was no significant difference between the number of pyknotic nuclei in trkA-/- and wild-type embryos at E11 and E12, there was a substantial increase in the number of pyknotic nuclei in the trigeminal ganglia of trkB-/- at these earlier stages. Counts of the total number of neurons in E13 trigeminal ganglia revealed a marked decrease in trkB-/- but not trkA-/- or trkC-/- embryos. Consistent with the later onset of excessive neuronal death in trkA-/- embryos, there was a marked decrease in the neuronal complement of the trigeminal ganglia of trkA-/- embryos at E15. These results demonstrate that TrkB signalling is required for the in vivo survival of many trigeminal neurons during the early stages of target field innervation before they become NGF-dependent.

Animals↗
PubMed2005

Globus pallidus neurons dynamically regulate the activity pattern of subthalamic nucleus neurons through the frequency-dependent activation of postsynaptic GABAA and GABAB receptors.

Reciprocally connected GABAergic neurons of the globus pallidus (GP) and glutamatergic neurons of the subthalamic nucleus (STN) are a putative generator of pathological rhythmic burst firing in Parkinson's disease (PD). Burst firing of STN neurons may be driven by rebound depolarization after barrages of GABA(A) receptor (GABA(A)R)-mediated IPSPs arising from pallidal fibers. To determine the conditions under which pallidosubthalamic transmission activates these and other postsynaptic GABARs, a parasagittal mouse brain slice preparation was developed in which pallidosubthalamic connections were preserved. Intact connectivity was first confirmed through the injection of a neuronal tracer into the GP. Voltage-clamp and gramicidin-based perforated-patch current-clamp recordings were then used to study the relative influences of GABA(A)R- and GABA(B)R-mediated pallidosubthalamic transmission on STN neurons. Spontaneous phasic, but not tonic, activation of postsynaptic GABA(A)Rs reduced the frequency and disrupted the rhythmicity of autonomous firing in STN neurons. However, postsynaptic GABA(B)Rs were only sufficiently activated to impact STN firing when pallidosubthalamic transmission was elevated or pallidal fibers were synchronously activated by electrical stimulation. In a subset of neurons, rebound burst depolarizations followed high-frequency, synchronous stimulation of pallidosubthalamic fibers. Although GABA(B)R-mediated hyperpolarization was itself sufficient to generate rebound bursts, coincident activation of postsynaptic GABA(A)Rs produced longer and more intense burst firing. These findings elucidate a novel route through which burst activity can be generated in the STN, and suggest that GABARs on STN neurons could act in a synergistic manner to generate abnormal burst activity in PD.

2-Amino-5-phosphonovalerate↗
PubMed2006

DNA polymerase-beta is expressed early in neurons of Alzheimer's disease brain and is loaded into DNA replication forks in neurons challenged with beta-amyloid.

Cultured neurons exposed to synthetic beta-amyloid (Abeta) fragments reenter the cell cycle and initiate a pathway of DNA replication that involves the repair enzyme DNA polymerase-beta (DNA pol-beta) before undergoing apoptotic death. In this study, by performing coimmunoprecipitation experiments on cross-linked nucleoprotein fragments from Abeta-treated neurons, we demonstrate that DNA pol-beta coimmunoprecipitates with cell division cycle 45 (Cdc45) and with DNA primase in short nucleoprotein fragments. This indicates that DNA pol-beta is loaded into neuronal DNA replication forks after Abeta treatment. In response to Abeta the canonical DNA-synthesizing enzyme DNA pol-delta also was loaded into neuronal replication forks, but at later times than DNA pol-beta. Methoxyamine, an inhibitor of the apurinic/apyrimidinic endonuclease that allows for the recruitment of DNA pol-beta during the process of base excision repair (BER), failed to affect coimmunoprecipitation between DNA pol-beta and Cdc45, indicating that DNA pol-beta loading to the replication forks is independent of DNA breaks. However, methoxyamine reduced DNA replication and ensuing apoptosis in neurons exposed to Abeta, suggesting that an efficient BER process allows DNA replication to proceed up to the threshold for death. These data demonstrate that DNA pol-beta is an essential component of the DNA replication machinery in Abeta-treated neurons and additionally support the hypothesis of a close association of cell cycle events with neuronal death in Alzheimer's disease (AD). Accordingly, by investigating the neuronal expression of DNA pol-beta, along with phosphorylated retinoblastoma protein and neurofibrillary changes in AD brain, we show an early involvement of DNA pol-beta in the pathogenesis of AD.

Adult↗
PubMed2001

Intrinsic factors involved in the depression of neuronal activity induced by temperature increase in rat hippocampal neurons.

The intrinsic factors involved in the temperature-dependent impairment of neuronal activity in hippocampal CA2-CA1 regions were investigated using optical recording techniques. At 32 degrees C, stimulation of the Schaffer collaterals in the hippocampal CA2 region evoked depolarizing optical responses that spread toward the CA1 region. The optical response was characterized by fast and slow components that were mainly related to the presynaptic action potentials and excitatory postsynaptic response, respectively. The increase of the temperature to 38 degrees C was associated with a reversible depression of the neuronal activity in the hippocampal brain preparations. The depression of neuronal activity was irreversible when the temperature was increased to 40 degrees C. In the presence of 22 mM glucose, the depression of the neuronal activity at 38 degrees C was significantly attenuated. Pyruvate (22 mM), but not lactate (22 mM), also improved the depression of neuronal activity induced by the temperature increase. Adenosine (200 microM) strongly depressed the excitatory postsynaptic response, but not presynaptic action potentials. 8-Cyclopentyl-1,3-dimethylxanthine (8-CPT) (10 microM), an adenosine A1 receptor blocker, attenuated the adenosine-induced depression of the excitatory postsynaptic response. 8-CPT (10 microM) prevented the impairment of the excitatory postsynaptic response induced by the increase of the temperature to 38 degrees C. In contrast, the depression of presynaptic action potential at 38 degrees C was not prevented by 8-CPT (10 microM). N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, and methylcobalamin (10 microM), a vitamin B12 analogue, attenuated the inhibition of pre- and postsynaptic activities induced by the increase of the temperature to 38 degrees C. Glibenclamide, a KATP channel blocker, did not protect neuronal activity from the effects of the increase of the temperature. These results suggest that the heat-induced depression of neuronal activity is mediated by multiple factors, such as impairment of energy metabolism and increase in extracellular adenosine and nitric oxide (NO) levels in hippocampal neurons.

Adenosine↗
PubMed1989

Sexually dimorphic neurons in the terminalia of Drosophila melanogaster: I. Development of sensory neurons in the genital disc during metamorphosis.

The adult terminalia of Drosophila melanogaster males and females are sexually dimorphic. The sensory neurons that innervate the sex-specific bristles of the analia and genitalia arise within the genital disc during metamorphosis. Using antibodies that recognize peripheral neurons, I have followed the development of neurons in the female genital, the male genital and the shared anal primordium. Neurons form only in the expressed genital and anal primordium at the onset of the white prepupal stage. Two basic types of neurons differentiate in the genital disc; exteroreceptors that innervate the external bristles and enteroreceptors that innervate the internal reproductive organs. Within the genital disc, each structure has a sex-specific time during pupation when its neurons differentiate even when neurons are derived from homologous primordia. The data suggest that the sexually dimorphic arrangement of sensory neurons is a product of sex-specific neurogenesis.

Animals↗
PubMed2000

Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review).

Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease, is a fatal neurological disease that is characterized clinically by progressive muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of ALS is primary degeneration of upper (motor cortical) and lower (brainstem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Very recent studies have identified that the degeneration of motor neurons in ALS is a form of apoptotic cell death that may occur by an abnormal programmed cell death (PCD) mechanism. In order to treat ALS effectively, we need to understand the mechanisms for motor neuron apoptosis more completely. Future studies need to further identify the signals for PCD activation in neurons as they relate to the pathogenesis of ALS and to clarify the molecular pathways leading to motor neuron apoptosis in animal and cell culture model systems. These studies should lead to a better understanding of motor neuron death and to the design of new therapeutic experiments critical for the future treatment of ALS.

Amyotrophic Lateral Sclerosis↗
PubMedDate not supplied

Integrative properties of the Pe1 neuron, a unique mushroom body output neuron.

A mushroom body extrinsic neuron, the Pe1 neuron, connects the peduncle of the mushroom body (MB) with two areas of the protocerebrum in the honeybee brain, the lateral protocerebral lobe (LPL) and the ring neuropil around the alpha-lobe. Each side of the bee brain contains only one Pe1 neuron. Using a combination of intracellular recording and neuroanatomical techniques we analyzed its properties of integrative processing of the different sensory modalities. The Pe1 neuron responds to visual, mechanosensory, and olfactory stimuli. The responses are broadly tuned, consisting of a sustained increase of spike frequency to the onset and offset of light flashes, to horizontal and vertical movements of extended objects, to mechanical stimuli applied to the antennae or mouth parts, and to all olfactory stimuli tested (29 chemicals). These multisensory properties are reflected in its dendritic organization. Serial reconstructions of intracellularly stained Pe1 neurons using confocal microscopy reveal that the Pe1 neuron arborizes throughout all layers of MB peduncle with finger-like, vertically oriented dendrites. The peduncle of the MB is formed by the axons of Kenyon cells, whose dendritic inputs are organized in modality-specific subcompartments of the calyx region. The peduncular arborization indicates that the Pe1 neuron receives input from Kenyon cells of all calycal subcompartments. Because the Pe1 neuron changes its odor responses transiently as a consequence of olfactory learning, we hypothesize that the multimodal response properties might have a role in memory consolidation and help to establish contextual references in the long-term trace.

Adaptation, Physiological↗
PubMed2000

Transplanted neuroblasts differentiate appropriately into projection neurons with correct neurotransmitter and receptor phenotype in neocortex undergoing targeted projection neuron degeneration.

Reconstruction of complex neocortical and other CNS circuitry may be possible via transplantation of appropriate neural precursors, guided by cellular and molecular controls. Although cellular repopulation and complex circuitry repair may make possible new avenues of treatment for degenerative, developmental, or acquired CNS diseases, functional integration may depend critically on specificity of neuronal synaptic integration and appropriate neurotransmitter/receptor phenotype. The current study investigated neurotransmitter and receptor phenotypes of newly incorporated neurons after transplantation in regions of targeted neuronal degeneration of cortical callosal projection neurons (CPNs). Donor neuroblasts were compared to the population of normal endogenous CPNs in their expression of appropriate neurotransmitters (glutamate, aspartate, and GABA) and receptors (kainate-R, AMPA-R, NMDA-R. and GABA-R), and the time course over which this phenotype developed after transplantation. Transplanted immature neuroblasts from embryonic day 17 (E17) primary somatosensory (S1) cortex migrated to cortical layers undergoing degeneration, differentiated to a mature CPN phenotype, and received synaptic input from other neurons. In addition, 23.1 +/- 13.6% of the donor-derived neurons extended appropriate long-distance callosal projections to the contralateral S1 cortex. The percentage of donor-derived neurons expressing appropriate neurotransmitters and receptors showed a steady increase with time, reaching numbers equivalent to adult endogenous CPNs by 4-16 weeks after transplantation. These results suggest that previously demonstrated changes in gene expression induced by synchronous apoptotic degeneration of adult CPNs create a cellular and molecular environment that is both permissive and instructive for the specific and appropriate maturation of transplanted neuroblasts. These experiments demonstrate, for the first time, that newly repopulating neurons can undergo directed differentiation with high fidelity of their neurotransmitter and receptor phenotype, toward reconstruction of complex CNS circuitry.

Animals↗
PubMed2001

Suppression of neuronal hyperexcitability and associated delayed neuronal death by adenoviral expression of GABA(C) receptors.

The excessive neuronal excitation underlying several clinically important diseases is often treated with GABA allosteric modulators in an attempt to enhance inhibition. An alternative strategy would be to enhance directly the sensitivity of postsynaptic neurons to GABA. The GABA(C) receptor, normally found only in the retina, is more sensitive to GABA and demonstrates little desensitization compared with the GABA(A) receptor. We constructed an adenovirus vector that expressed cDNA for both the GABA(C) receptor rho(1) subunit and a green fluorescent protein (GFP) reporter and used it to transduce cultured hippocampal neurons. Transduced neurons were identified by fluorescence, double immunocytochemistry proved colocalization of the rho(1) protein and the reporter, Western blot verified the expected molecular masses, and electrophysiological and pharmacological properties confirmed the presence of functional GABA(C) receptors. rho(1)-GFP transduction resulted in an increased density of GABA(A) receptors as well as expression of novel GABA(C) receptors. This effect was not reproduced by addition of TTX or Mg(2+) to the culture medium to reduce action potentials or synaptic activity. In a model of neuronal hyperexcitability induced by chronic blockade of glutamate receptors, expression of GABA(C) receptors abolished the hyperactivity and the consequent delayed neuronal death. Adenovirus-mediated neuronal GABA(C) receptor engineering, via its dual mechanism of inhibition, may offer a way of inhibiting only those hyperexcitable neurons responsible for clinical problems, avoiding the generalized nervous system depression associated with pharmacological therapy.

Action Potentials↗
PubMed2001

[Combined neuronal toxicity of bilirubin and hypoxia. Study of cultured rat neurons].

UNLABELLED: Clinical observations suggest that bilirubin encephalopathy is often seen in newborn infants presenting not only with hyperbilirubinemia but also with alterations in oxygen transport like in severe anaemia. Since bilirubin and hypoxia have been shown to be detrimental to the central nervous system, the present study was designed to test the additional effects of the two insults on the outcome of cultured neurons from the forebrain of 14 day-old embryos. After 6 days in vitro, neurons were exposed either to bilirubin (0.5 microM) or to bilirubin and hypoxia for 6 hours. Thereafter, cells were reoxygenated for 96 hours in standard conditions. Control cells were kept in normoxia. Cell viability was assessed by the methyltetrazolium method. Cell death (apoptosis or necrosis) was characterized by fluorescent nuclear staining with DAPI. Rates of protein synthesis and energy metabolism in neurons were measured by [3H]leucine and [3H]2-deoxyglucose incorporation, respectively. Data are reported as percentages of change as compared to controls. Each experiment involved 5 to 10 dishes per time point and was repeated 2 to 4 times. RESULTS: Bilirubin reduced cell viability by 24.5% vs controls (p < 0.001) at 96 h while 16% of the neurons exhibited morphological features of apoptosis (p < 0.001). The combination of hypoxia with bilirubin induced a 34% decrease in cell viability (p < 0.001) and the percentage of apoptotic cells was higher than after the exposure to hypoxia or to bilirubin alone. The rate of protein synthesis increased significantly in all experimental conditions as early as 1 h after the onset of the insult and at 48 h post reoxygenation. It increased again at 72 h in the cells exposed to bilirubin or to bilirubin and hypoxia. These sequential changes in synthesis of specific proteins seem to be involved in delayed neuronal death. Bilirubin decreased significantly [3H]2-deoxyglucose incorporation at 24 h while it increased when the neurons were exposed to both bilirubin and hypoxia (+60%, p < 0.001) and decreased thereafter. These data confirm the deleterious effects of bilirubin on neuronal viability, on protein synthesis and metabolic rates. The combination of bilirubin with hypoxia resulted in stronger detrimental effects on neurons than bilirubin alone.

Animals↗
PubMedDate not supplied

Herpes simplex latent infection: quantitation of latency-associated transcript-positive neurons and reactivable neurons.

Dorsal root ganglion neurons, which express herpes simplex virus (HSV) latency-associated transcript (LAT) during experimental latent infection, were investigated by in situ hybridization. The number of LAT-positive neurons was determined by examination of ganglion serial sections. In other latently infected mice, the number of ganglion neurons that reactivated HSV antigen after explant culture was determined in serial sections. LAT was detected in 100 percent of ganglia, with an average of 19.5 LAT-positive neurons per ganglion. After explant culture of latently infected ganglia (in the presence of colchicine to decrease spread of reactivated virus), HSV antigen was detected in 94 percent of ganglia, with an average of 13.1 positive neurons in the antigen-positive ganglia. The similar quantities of LAT- and antigen-positive neurons within ganglia support the hypothesis that LAT-positive neurons were the neurons from which HSV was reactivated.

Animals↗
PubMed1989

An immunohistochemical study of neuropeptides and neuronal cytoskeletal proteins in the neuroepithelial component of a spontaneous murine ovarian teratoma. Primitive neuroepithelium displays immunoreactivity for neuropeptides and neuron-associated beta-tubulin isotype.

Approximately one third of the female mice of the LTXBO strain develop spontaneous ovarian teratomas. These tumors contain a large neuroepithelial component, which includes primitive neural structures resembling embryonic neural tubes (medulloepithelial rosettes), ependymoblastic and ependymal rosettes, neuroblasts, mature ganglionic neurons, myelinated neurites, and astrocytes. The purpose of this study was to characterize these tumors according to the immunohistochemical location of some well-characterized trophic and regulatory neuropeptides and neurotransmitters, several neuronal-associated cytoskeletal proteins, and other proteins indicative of neuronal and glial differentiation. Medulloepithelial rosettes showed focal serotonin-like, opioid peptide-like and gamma-amino butyric acid-like immunoreactivity, and displayed immunostaining for the neuron-associated class III beta-tubulin isotype. The mature ganglion cells were also immunoreactive for these markers, and, in addition, for somatostatin, cholecystokinin, bombesin, glucagon, vasoactive intestinal peptide, and neuropeptide Y. Mature ganglion cells were also immunoreactive for proteins associated with the neuronal cytoskeleton (including microtubule-associated proteins, MAP2 and tau, and higher molecular weight phosphorylated and non-phosphorylated neurofilament subunits), neuron-specific enolase, and synaptophysin. Undifferentiated stem cells, ependymoblastic and ependymal rosettes, and astroglia all stained with a monoclonal antibody that recognizes all mammalian beta-tubulin isotypes, but did not react with antibodies to neuronal-associated cytoskeletal proteins or neuropeptides. Neuropeptide-like immunoreactivity and demonstration of the class III beta-tubulin isotype indicate early neuronal commitment in neoplastic primitive neuroepithelium. These patterns of immunoreactivity closely follow those encountered in the normal neurocytogenesis of the mammalian and avian forebrain, and increase the precision with which the early stages of progressive neuroepithelial differentiation can be analyzed in human embryonal tumors of the CNS.

Animals↗
PubMed1986

Fodrin degradation by calcium-activated neutral proteinase (CANP) in retinal ganglion cell neurons and optic glia: preferential localization of CANP activities in neurons.

The activity of calcium-activated neutral proteinases (CANPs) toward endogenous substrates was measured in axons of retinal ganglion cell (RGC) neurons and separately in adjacent optic glia under in vitro conditions that preserved the ultrastructure and anatomic relationships between these cellular elements. RGC neurons and optic glia both expressed CANP activity. In contrast to RGC axons, which contained at least two CANP activities with calcium requirements in the millimolar (CANP A) and micromolar (CANP B) range (Nixon et al., 1985), CANP activity in optic glia was detectable only at millimolar calcium concentrations. When maximally activated, CANP(s) in optic glia exhibited a broad specificity for endogenous proteins but degraded larger proteins at a faster rate. The cytoskeletal protein fodrin (brain spectrin) was among the most susceptible endogenous substrates in RGC axons or glia. The similar properties of fodrin in neurons and glia, including its susceptibility to a purified millimolar calcium-sensitive brain CANP (mCANP), provided the basis for using this protein as a substrate to compare the relative activity of neuronal and glial CANPs in situ. Fodrin degradation mediated by CANPs proceeded at least 6 X more rapidly in intact RGC axons than in optic glia. Comparable differences in the relative degradation rates of the total neuronal and glial protein pools were also observed. These results indicate that the potential activity of CANPs is substantially greater in RGC neurons than in glia. The enormous potential activity and preferential localization of multiple CANP activities in RGC neurons support previously hypothesized roles for CANPs in the processing of axonally transported proteins and in the regulation of neuronal cytoskeletal dynamics and geometry.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Neuronal cell surfaces: distinctive glycoproteins of cultured adrenergic and cholinergic sympathetic neurons.

Cell surface components which are candidates for a role in nerve-target interactions specific for neurons of particular transmitter types in the sympathetic nervous system have been identified. Neurons of superior cervical ganglia of neonatal rats were dissociated and cultured in the virtual absence of non-neuronal cells under conditions previously found to control their choice of neurotransmitter. When raised in medium conditioned by heart cells, the neurons become cholinergic; when raised in medium which depolarizes them, the neurons remain in their original adrenergic state. The cell surface proteins of the neurons were labeled by either metabolic or surface-specific methods, separated by two-dimensional polyacrylamide gel electrophoresis, and visualized by autoradiography. A total of approximately 35 glycoproteins can be resolved, of which at least 14 are exposed on the cell surface. We evaluated glycoproteins of neurons raised under conditions which differ in their potency for inducing cholinergic properties: medium conditioned by skeletal muscle, liver, or heart cells or medium containing 1 mM butyric acid. The expression of three neuronal glycoproteins was correlated with the ability of a given culture condition to induce the synthesis and accumulation of acetylcholine or catecholamines. Two of these proteins are exposed on the cell surface, and the third appears to be identical with a protein previously shown to be secreted into the culture medium.

Acetylcholine↗
PubMed1994

Nuclear-encoded mitochondrial precursor protein: intramitochondrial delivery to dendrites and axon terminals of neurons and regulation by neuronal activity.

Mitochondria contain hundreds of proteins, most of which are encoded by the nucleus. In neurons, distal dendrites and axon terminals can be separated from the nucleus by a great distance, and the mechanism by which precursor proteins reach distal neuronal processes is not well understood. While our previous study on cytochrome oxidase suggests a post-translational mechanism of delivery, it is not known whether precursor proteins reach their target processes before or after incorporation into mitochondria. In order to localize only precursor proteins and not the mature form of the subunit in neurons, we generated polyclonal antibodies against synthetic presequence polypeptides specific to nuclear-encoded subunit IV precursor protein of rat brain cytochrome oxidase. We found that the precursors were located not only in neuronal cell bodies, but also in dendrites and axon terminals. This indicates that the conversion of these precursors to their mature form is not confined to the cell body but occurs in dendrites and axons as well. At the electron microscopic level, an overwhelming majority of immunoreaction product was found within mitochondria, suggesting that precursor proteins are transported to neuronal processes mainly within mitochondria, and that their half-lives are much longer in neurons than in yeast and rat hepatocytes. The precursor pool was downregulated in the rat superior colliculus after monocular enucleation, indicating that precursor synthesis and/or degradation is regulated by neuronal functional activity. These results also suggest that local functional demands may play an important role in controlling the processing of precursors and the assembly of holoenzymes in dendrites and axon terminals. This allows neurons to regulate enzyme levels locally, precisely, and rapidly.

Animals↗
PubMed1997

Self-injurious behavior and dopaminergic neuron system in neonatal 6-hydroxydopamine-lesioned rat: 1. Dopaminergic neurons and receptors.

Dopaminergic neuronal circuits underlying self-injurious behavior (SIB) were investigated in neonatal 6-hydroxydopamine (6-OHDA)-induced dopamine-depleted rats. The extent of damaged dopamine neuronal areas was investigated by quantitative analysis of tyrosine hydroxylase (TH) immunocytochemistry and the biochemical quantification of dopamine levels in three groups; neonatal 6-OHDA-treated rats showing SIB (the SIB(+) group), neonatal 6-OHDA-treated rats not showing SIB (SIB(-) group) and neonatal saline-treated controls (control group). In the SIB(+) group, both dorsal and ventral mesostriatal dopaminergic neuron systems were severely destroyed, but the mesocortical dopaminergic neuron system and intrahypothalamic dopaminergic neuron system remained intact. In SIB(-) group, the dorsal mesostriatal dopaminergic neuron system was severely destroyed, but the ventral mesostriatal dopaminergic neuron system was only partially impaired. The effect of neonatal 6-OHDA treatment on dopaminergic receptors was analyzed by quantitative in vitro receptor autoradiography using [3H]SCH-23390 for the D1 site and [3H]YM-09151-2 for the D2 site. Although D1 and D2 binding was not altered in the dorsal and ventral striatum, cerebral cortex and hypothalamus, the D1 binding in the substantia nigra pars reticulata was increased in the SIB(+) group compared with the SIB(-) or control groups. The D1 binding assay using the membrane preparation of the nigral homogenates, revealed that the KD did not change, but the Bmax in the SIB(+) group was higher than that in the SIB(-) or control groups (P < .05). These results suggest that the region-specific change of dopaminergic neurons and receptors underlies the manifestation of SIB.

Animals↗
PubMed1997

Prevention of normally occurring and deafferentation-induced neuronal death in chick brainstem auditory neurons by periodic blockade of AMPA/kainate receptors.

The role of glutamate receptors in regulating programmed neuronal death and deafferentation-induced neuronal death in the brainstem auditory nuclei was studied by in ovo drug administration to chick embryos. The nucleus laminaris (NL) undergoes programmed developmental cell death of 19% between embryonic day 9 (E9) and E17. The AMPA/kainate receptor antagonist CNQX, when administered at doses of 200-300 microg/d from E8 to E15, prevented programmed neuronal death in NL through at least posthatching day 8, without producing anatomical or behavioral abnormalities. 3-((RS)-2-Carboxypiperazin-4-yl)-propyl-1-phos-phonic acid, an antagonist of NMDA receptors, had no effect on normal cell death in the NL. CNQX, given from E8 to E15 or only from E8 to E10, also blocked the 33% neuronal loss in the nucleus magnocellularis (NM) that follows surgical destruction of the otocyst on E3, a procedure that deafferents NM neurons by preventing formation of the cochlear nerve. Treatment either with CNQX or the more highly selective NBQX from E8 to E10, before the onset of synaptic transmission in NM and NL, was also effective in preventing normal neuronal death in NL. Analysis of the effects of CNQX or NBQX on spontaneous embryonic motility at E10 showed that the doses effective in preventing neuronal death suppressed motility for <8 hr. We conclude that periodic blockade of AMPA/kainate receptors can protect CNS neurons against subsequent programmed cell death or deafferentation-induced death.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Metabolism of acetate in rat brain neurons, astrocytes and cocultures: metabolic interactions between neurons and glia cells, monitored by NMR spectroscopy.

The existence of metabolic compartmentation is generally accepted for the brain because of the specific differences in glial and neuronal metabolism. Extracellularly supplied acetate is believed to serve as a substrate only for glia cells, but not for neurons. To further test this hypothesis, primary rat brain cultures of neurons, astrocytes, and cocultures of both cell types were used to investigate the metabolic fate of [2-13C]acetate by means of nuclear magnetic resonance (NMR) spectroscopy. Acetate was metabolized by both cell types, neurons and astrocytes in culture. While glutamine was the main product of glial metabolism, labelled glutamate and aspartate were detected in neuron cultures. Astrocytes and neurons in cocultures showed a very different picture, which is similar to results obtained from brain slices, or in vivo studies. The analysis of the isotopomer pattern of glutamate and glutamine confirm an active glutamate-glutamine-cycle between neurons and astrocytes in cocultures. Furthermore, the analysis of unlabelled metabolites revealed a metabolic coupling of hypotaurine and taurine metabolism in astrocytes and neurons, which provides both cell types with one of the most important organic osmolytes.

Acetates↗