Some metabolic effects on primary cultures of neurons or astrocytes were studied following acute or chronic exposure to pathophysiological concentrations (usually 3 mM) of ammonia. Three parameters were investigated: (1) 14CO2 production from 14C-labeled substrates [glucose, pyruvate, branched-chain amino acids (leucine, valine, isoleucine), and glutamate]; (2) interconversion between glutamate and glutamine; and (3) incorporation of label from labeled branched-chain amino acids into proteins. Neither acute nor chronic exposure to ammonia had any effect on 14CO2 production from [U-14C]glucose in astrocytes and neurons, whereas under certain conditions 14CO2 production from [1-14C]pyruvate in astrocytes was inhibited by ammonia. Production of 14CO2 from [1-14C]branched-chain amino acids was inhibited by acute, but stimulated by chronic, exposure to ammonia (3 mM) in astrocytes, with less effect in neurons. Production of 14CO2 from [1-14C]glutamate in both astrocytes and neurons was inhibited by acute exposure to ammonia. In astrocytes, glutamate levels tended to decrease and glutamine levels tended to increase following acute exposure to ammonia; in neurons, both glutamine and glutamate levels decreased. Protein content (per culture dish) increased in astrocytes but not in neurons, after chronic exposure to ammonia, possibly as a result of enhanced protein synthesis and/or by inhibition of protein degradation.

Amino Acids↗

PubMedDate not supplied

Is Alzheimer's disease an anterograde degeneration, originating in the brainstem, and disrupting metabolic and functional interactions between neurons and glial cells?

A novel hypothesis is suggested for the pathogenesis of Alzheimer's disease, i.e. that a degeneration of adrenergic neurons in locus coeruleus and/or of serotonergic neurons in the raphe nuclei leads to impairment in metabolic and functional interactions between neurons and astrocytes (in the cerebral cortex and hippocampus as well as in nucleus basalis magnocellularis), and that a resulting deficient supply of substrates and failing energy metabolism in both neurons and astrocytes causes neuronal cell death in these areas and thus interference with additional transmitter systems. The hypothesis is based on (1) the topographical distribution of ascending pathways from locus coeruleus and the raphe nuclei; (2) the peculiar termination of many of these fibres in varicosities, from which released transmitter molecules reach their targets by diffusion, rather than in genuine synapses, suggesting a partly non-neuronal target; (3) the effects of locus coeruleus lesions in experimental animals; (4) the emergence of new knowledge in cellular neurobiology, indicating profound metabolic and functional interactions between neurons and astrocytes; and (5) the effects of adrenergic and serotonergic agonists upon metabolism and function in rodent astrocytes and neurons. These compounds influence energy metabolism, membrane transport of potassium and production of growth factors in astrocytes, and glutamate release from glutamatergic neurons. They thus influence essential metabolic interactions between neurons and astrocytes, as well as neuronal-astrocytic interactions in potassium homeostasis at the cellular level. Obviously, neither the individual findings alone, nor their combination into a conceptual framework, prove the correctness of the hypothesis. However, they do provide a basis for further experimental work, using postmortem brain tissue from Alzheimer's patients and lesion studies in rodents, which can confirm or refute the hypothesis.

Alzheimer Disease↗

PubMedDate not supplied

Autonomic control of neuronal-astrocytic interactions, regulating metabolic activities, and ion fluxes in the CNS.

It is generally assumed that the brain, in contrast to all other organs, is not equipped with an autonomic nervous system, regulating blood supply, and cellular activities. This may be because systemic administration of most drugs acting on monoaminergic or cholinergic receptors have little or no effect on cerebral blood flow and metabolism. However, intrathecal administration of noradrenaline does, indeed, influence both blood flow and energy metabolism in the brain. The present review focuses on effects of noradrenaline or serotonin on energy metabolism, turnover of amino acid transmitters and ion homeostasis, with special emphasis on the cellular localization. Noradrenergic agonists stimulate brain metabolism in vivo as well as many aspects of energy metabolism, Na+,K(+)-ATPase activity and uptake of transmitter amino acids in astrocytes in primary cultures, with little or no effect on corresponding preparations of neurons. Serotonin acts differently, decreasing potassium-induced release of glutamate from both neurons and astrocytes. Little is known about the effects of acetylcholine. The functional significance of these effects is discussed.

Animals↗

PubMedDate not supplied

What do retinal müller (glial) cells do for their neuronal 'small siblings'?

Müller (radial glial) cells are the predominant glia of the vertebrate retina. They arise, together with rod photoreceptor cells, bipolar cells, and a subset of amacrine cells, from common precursor cells during a late proliferative phase. One Müller cell and a species-specific number of such neurons seem to form a columnar unit within the retinal tissue. In contrast, 'extracolumnar neurons' (ganglion cells, cone photoreceptor cells, horizontal cells, and another subset of amacrine cells) are born and start differentiation before most Müller cells are generated. It may be essential for such neurons to develop metabolic capacities sufficient to support their own survival, whereas late-born ('columnar') neurons seem to depend on a nursing function of their 'sisterly' Müller cell. Thus, out of the cell types within a retinal column it is exclusively the Müller cell that possesses the enzymes for glycogen metabolism. We present evidence that Müller cells express functional insulin receptors. Furthermore, isolated Müller cells rapidly hydrolyse glycogen when they are exposed to an elevated extracellular K+ ion concentration, a signal that is involved in the regulation of neuronal-glial metabolic cooperation in the brain. Müller cells are also thought to be essential for rapid and effective retinal K+ homeostasis. We present patch-clamp measurements on Müller cells of various vertebrate species that all demonstrate inwardly rectifying K+ channels; this type of channel is well-suited to mediate spatial buffering currents. A mathematical model is presented that allows estimation of Müller cell-mediated K+ currents. A simulation analysis shows that these currents greatly limit lateral spread of excitation beyond the borders of light-stimulated retinal columns, and thus help to maintain visual acuity.

Animals↗

PubMedDate not supplied

Neuronal-astrocytic and cytosolic-mitochondrial metabolite trafficking during brain activation, hyperammonemia and energy deprivation.

A novel concept is described, according to which both neurons and astrocytes are capable of metabolizing glucose all the way to CO(2) and water, but in addition interact metabolically in a process generating glutamate from glucose, and subsequently, metabolizing excess glutamate to CO(2) and water Hertz, L., Dringen, R., Schousboe, A., Robinson, S.R., 1999. Astrocytes: Glutamate producers for neurons (Journal of Neuroscience Research 57, 417-428). The proposed metabolic degradation of glucose via glutamate serves the purpose of adjusting transmitter pools of glutamate to the demands for glutamatergic transmission, and it must account for a major fraction of glucose utilization. Evidence in favor of this concept is presented and a multitude of in vivo data are interpreted in the context of metabolic trafficking between neurons and astrocytes. In addition, intracellular trafficking occurs between cytosol and mitochondria during synthesis of transmitter glutamate, partly explaining a robust quantitative correlation between glutamine synthesis, as a measure of release of transmitter glutamate, and glucose utilization, reported by several authors. Both intracellular and intercellular metabolic trafficking may be affected during pathological conditions, as evidenced by effects of hyperammonemia (mimicking hepatic encephalopathy) and energy deprivation (mimicking stroke). It is suggested that neuronal-astrocytic interactions may also be impaired during degenerative dementing diseases.

Ammonia↗

PubMedDate not supplied

Metabolic fate of [U-14C]-labeled glutamate in primary cultures of mouse astrocytes as a function of development.

The metabolic fate of [U-14C]-labeled glutamate in astrocytes grown in primary cultures for 1-3 weeks in the absence or presence of dibutyryl cyclic AMP was followed using dansylation with 3H-dansyl chloride and subsequent thin layer chromatography of the dansylated amino acids. No indication was found of classical metabolic compartmentation, i.e., the specific radioactivity of glutamine (14C/3H ratio) never exceeded that of its precursor, glutamate. In accordance with a relatively late maturation of glutamine synthetase activity the rate of formation of labeled glutamine was much faster in 3-week-old than in 1-week-old cultures. The opposite was found for aspartate formation, but under all conditions incorporation of radioactivity into aspartate was pronounced.

Animals↗

PubMedDate not supplied

[Facial dysmorphism related to valproic acid ingestion during pregnancy].

The authors report a case of cranio-facial changes in a neonate who had been exposed to Valproate. Clinical picture consisted of hypoplastic fronto-orbital edges and microstomia. These abnormalities are compared with the series reported in the literature.

Abnormalities, Drug-Induced↗