Developmental Neuroscience

doi: 10.1159/000111328pmid: 7805566

Edmond, John

doi: 10.1159/000111329pmid: N/A

Tildon, J. Tyson

doi: 10.1159/000111330pmid: N/A

Williamson, Dermot H.; Lund, Patricia

doi: 10.1159/000111331pmid: 7805567

In the suckling neonate the source of lipid and other substrates for brain development is the mother''s milk. The lactating mammary gland is a highly versatile organ which is able to utilize a range of substrates for milk lipid production including glucose and ketone bodies (for de novo synthesis), triacylglycerols and non-esterified fatty acids. The composition of the milk lipid alters with changes in the substrates available to the mammary gland. The neonate has to process the milk triacylglycerols to forms (ketone bodies, medium-chain fatty acids) more suitable for extraction by the developing brain. The strategies employed to allow this flexibility in the lactating rat and its offspring are discussed.

McCormack, James G.; Denton, Richard M.

doi: 10.1159/000111332pmid: 7805568

The mitochondrial inner membrane of all mammalian tissues, including brain tissues, has specific active transport systems for the uptake and egress of Ca²⁺. The primary role of this transport system is to relay changes in cytosolic [Ca²⁺], which stimulates energy-requiring processes in the cytosol (e.g. secretion), into the mitochondrial matrix where it stimulates several key steps in energy production. Thus using the same second-messenger molecule, the latter events allow energetic homeostasis to be maintained under conditions of cell stimulation. This appears to be brought about by a co-ordinated enhancement of steps throughout the pathways of oxidative phosphorylation, including substrate supply to the respiratory chain by dehydrogenase activation, activation of the respiratory chain itself by a mechanism which appears to involve changes in the matrix volume, and also possibly activation of the ATP synthetase where the release of a specific inhibitory subunit has been proposed.

Clark, J.B.; Bates, T.E.; Cullingford, T.; Land, J.M.

doi: 10.1159/000111333pmid: 7805569

The metabolic capability for the complete oxidation of glucose, i.e. aerobic glycolysis, is highly developed in the brains of neurologically mature (precocial) species at birth, whereas this activity is severely limited in the brains of neurologically immature (non-precocial) species such as the rat and human. The latter utilize a mixture of glucose and ketone bodies for synthetic and energetic activities and the advent of neurological competence associated with the capability for complete dependence on and oxidation of glucose must await the development of key enzymes such as the pyruvate dehydrogenase complex (PDHC). A similar relationship appears to exist with respect to the development of neurological maturity of different brain regions in a single species, the rat. The development of the enzymes of energy metabolism of neonatal rat brain will be discussed with respect to the energy fuels available to the neonatal brain. In particular mechanisms by which the PDHC develops in neonatal brain will be evaluated. Evidence suggests that this is due to a specific increase in enzyme protein in contrast to a general increase in mitochondrial activity.

Lai, James C.K.; Behar, Kevin L.

doi: 10.1159/000111334pmid: 7805570

In the development of an integrated approach to study metabolic compartmentation and regulation in brain, we have emphasized the importance, versatility, and need to exploit the recent methodological advances in (1) NMR spectroscopy, (2) primary cultures of neurons and glial cells, and (3) subcellular fractionation (especially brain mitochondrial isolation). The integrated approach has the advantage of being able to draw data and inferences based on some combination of results derived from in vivo, cellular, and subcellular studies. For example, some in vivo NMR data may suggest that an enzymatic step may be rate-limiting in a particular pathway. This information may be used to frame testable hypotheses and questions that can be investigated in experiments involving primary cultures of neural cells and subcellular fractions. Subsequently, the data from such in vitro studies could serve as the bases for constructing the hypothetical framework for predicting the regulatory role, in vivo, of the enzyme in the pathway. We have discussed the known as well as the as yet ill-defined facets of the cellular and subcellular aspects of the glycolysis-citric acid cycle interrelation and have attempted to illustrate how such an integrated approach could be applied to generate testable hypotheses for investigating the mechanisms concerned with metabolic compartmentation and regulation in brain. In the process of the illustration, we discuss some of the evidence in support of the general hypothesis that the transfer of reducing equivalents across the inner mitochondrial membrane plays a major role in mediating the coupling of the glycolytic flux to that of the citric acid cycle. We have given some indications as to how this hypothesis could be further investigated employing our approach. Moreover, we hope that other workers will find this integrated approach useful in designing multidisciplinary studies to investigate mechanistic issues related to this important theme.

Sokoloff, Louis

doi: 10.1159/000111335pmid: 7805571

Traditional neuroanatomies and electrophysiological methods to localize functional activities in the nervous system focus on perikarya as the sites of activity. Metabolic mapping of local functional activity in the nervous system with the deoxyglucose method has directed interest toward the activity in neuropil. Studies of local glucose utilization (lCMR_glc) indicate that energy metabolism is increased by functional activation mainly in terminal projection zones of activated pathways. Electrical stimulation of a pathway raises lCMR_glc in the projection zones of the pathway in almost direct proportion to the spike frequency. For example, stimulation of the sciatic nerve produces frequency-dependent metabolic activation in the dorsal horn of the lumbar cord, where the axonal terminals of the afferent pathway reside, with no apparent metabolic effects in the cell bodies of the pathway in the dorsal root ganglia. Functional activation of the hypothalamo-hypophysial pathway by salt-loading increases lCMR_glc in the neurohypophysis, the site of the terminal axons of the pathway, but not in the paraventricular and supraoptic nuclei, where the cell bodies of origin of the pathway reside. Activation by hypotension of pathways to these nuclei from brain stem structures involved in baroceptor reflexes does, however, increase lCMR_glc in these nuclei. Depolarization induced by electrical stimulation, increased extracellular K⁺, or opening of Na ⁺ channels with veratridine stimulate lCMR_glc in neural tissues, and this increase is blocked by ouabain, a specific inhibitor of Na⁺, K⁺-ATPase. Activation of this enzyme to restore ionic gradients across cellular membranes appears to trigger the function-related increase in energy metabolism. The metabolic activation is the consequence not of the functional activity itself but of processes operating to recover from that activity.

Bachelard, Herman; Badar-Goffer, Ronnitte; Ben-Yoseph, Oded; Morris, Peter; Thatcher, Nicola

doi: 10.1159/000111336pmid: 7805572

The effects of hypoxia and hypoglycaemia on cerebral metabolism and calcium have been studied using multinuclear magnetic resonance spectroscopy. ¹³C MRS showed that severe hypoxia did not cause any further increase in metabolic flux into lactate seen in mild hypoxia, but there was a further increase in ¹³C labelling of alanine and glycerol 3-phosphate. These results are discussed in terms of the ability of lactate dehydrogenase to maintain normal levels of NADH in mild hypoxia, but not in severe hypoxia. We conclude that glycerol 3-phosphate and alanine may provide novel means of monitoring severe hypoxia whereas lactate is a reliable indicator only of mild hypoxia. ¹⁹F- and ³¹P NMR spectroscopy showed that neither hypoxia nor hypoglycaemia alone caused any significant change in [Ca²⁺]_i. Combined sequential insults (hypoxia, followed by hypoxia plus hypoglycaemia), or vice versa, produced a 100% increase in [Ca²⁺]_i, whereas immediate exposure to the combined insult (hypoxia plus hypoglycaemia) resulted in a large 5-fold increase in [Ca²⁺]_j, with severe irreversible effects on the energy state. These results are discussed in terms of metabolic adaptation to the single type of insult, which renders the tissue less vulnerable to the combined insult. The effects of this combined insult are far more severe than those caused by glutamate or NMDA, which throws doubt on the current excitoxic hypothesis of cell damage.

Walz, Wolfgang; Klimaszewski, Artur; Paterson, I. Alick

doi: 10.1159/000111337pmid: 7805573

On the basis of experiments with primary cultures of mouse astrocytes with conventional K⁺-sensitive intracellular microelectrodes involving ''chemical ischemia'' (antimycin a and sodium fluoride treatment), a model of ischemia is presented. According to this model, ischemia has no significant direct effect during the first 10 min on astrocytes; neurones, however, lose a major part of their K⁺ into the ECS. This leads to an astrocytic depolarization, which in turn activates astrocytic anion channels. This will result in passive, Donnan-mediated K⁺, CI^– and HCO3̄ fluxes into astrocytes, which in turn causes swelling and a collapse of the ECS. Arguments are put forward that this may explain the swelling of astrocytic endfeet, which occurs very early in an ischemic insult.