Brain-derived neurotrophic factor (BDNF) promotes the biochemical and morphological differentiation of selective populations of neurons during development. In this study we examined the energy requirements associated with the effects of BDNF on neuronal differentiation. Because glucose is the preferred energy substrate in the brain, the effect of BDNF on glucose utilization was investigated in developing cortical neurons via biochemical and imaging studies. Results revealed that BDNF increases glucose utilization and the expression of the neuronal glucose transporter GLUT3. Stimulation of glucose utilization by BDNF was shown to result from the activation of Na+/K+-ATPase via an increase in Na+ influx that is mediated, at least in part, by the stimulation of Na+-dependent amino acid transport. The increased Na+-dependent amino acid uptake by BDNF is followed by an enhancement of overall protein synthesis associated with the differentiation of cortical neurons. Together, these data demonstrate the ability of BDNF to stimulate glucose utilization in response to an enhanced energy demand resulting from increases in amino acid uptake and protein synthesis associated with the promotion of neuronal differentiation by BDNF.

Dendritic development is essential for the establishment of a functional nervous system. Among factors that control dendritic development, brain-derived neurotrophic factor (BDNF) has been shown to regulate dendritic length and complexity of cortical neurons. However, the cellular and molecular mechanisms that underlie these effects remain poorly understood. In this study, we examined the role of amino acid transport in mediating the effects of BDNF on dendritic development. We show that BDNF increases System A amino acid transport in cortical neurons by selective up-regulation of the sodium-coupled neutral amino acid transporter (SNAT)1. Up-regulation of SNAT1 expression and System A activity is required for the effects of BDNF on dendritic growth and branching of cortical neurons. Further analysis revealed that induction of SNAT1 expression and System A activity by BDNF is necessary in particular to enhance synthesis of tissue-type plasminogen activator, a protein that we demonstrate to be essential for the effects of BDNF on cortical dendritic morphology. Together, these data reveal that stimulation of neuronal differentiation by BDNF requires the up-regulation of SNAT1 expression and System A amino acid transport to meet the increased metabolic demand associated with the enhancement of dendritic growth and branching.Development of the nervous system proceeds through a sequence of complex ontogenetic processes that includes cell proliferation, migration, neurite outgrowth, axon guidance, and synapse formation (1). Neuronal development is determined by both intrinsic and extrinsic factors. Among the latter, neurotrophic factors play a key role. In particular, BDNF, 2 a member of the neurotrophin family, controls the survival and differentiation of specific neuronal populations in the peripheral and central nervous system (2). In the developing visual cortex, BDNF has been shown to regulate the dendritic growth and complexity of pyramidal neurons (3, 4). Furthermore, overexpression of BDNF in pyramidal neurons of the visual cortex leads to sprouting of basal dendrites and regression of dendritic spines (5). Because dendritic morphology determines the number, pattern, and types of synapses received by a neuron, regulation of cortical dendritic growth and branching by BDNF is likely to play a major role for the proper functioning of the brain and especially the cerebral cortex.Although BDNF regulates cortical dendritic development, little is known about the cellular and molecular mechanisms underlying these effects. In particular, the role of amino acid transport in mediating the effects of BDNF on dendritic growth and branching remains unknown.System A is a ubiquitous amino acid transport system that mediates the Na ϩ -dependent transport of short-chain neutral amino acids such as alanine, serine, and glutamine (6). In addition, System A is the major amino acid transport system subject to regulation by environmental conditions, proliferative stimuli, developmental changes, hormones, and growth factors (6). Durin...

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1. Thirty-four patients with essential hypertension and 37 with proven renovascular hypertension were tested with saralasin after frusemideinduced diuresis.2. Variables used for analysis were: presaralasin plasma renin activity (PRA), postsaralasin PRA, and ratios of systolic and diastolic blood pressures (saralasin blood pressure/control blood pressure).3. Stepwise linear discriminant analysis demonstrated that the most significant variables were diastolic ratio, systolic ratio, and post-saralasin PRA.4. Minimal misclassification (14.1%) was achieved by combining diastolic ratio, baseline supine PRA and post-saralasin PRA; but using post-saralasin PRA alone resulted in misclassification of only 15.5% (7 essential hypertension and 4 renovascular hypertension). 5. Thus, PRA increased disproportionately after saralasin in renin-dependent renovascular hypertension because of the fall in blood pressure and/or interruption of the short, negative angiotensin I1 feedback loop.6. It is concluded that the rise in PRA after the combined stimuli of volume depletion and saralasin is more sensitive than the fall in blood pressure in discriminating between essential hypertension and renovascular hypertension, although minimal misclassification is achieved by analysing baseline PRA, diastolic ratio and post-saralasin PRA simultaneously.