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IN RECENT studies of glutamic acid metabolism in uivo, the fate of tracer amounts of rqlabelled glutamic acid administered intravenously to rats and mice was investigated in experiments of short duration (LAJTHA, BERL and WAELSCH, 1959). The major portion of the amino acid apparently entered brain, liver, kidney and muscle as the acid and conversion to the amide was not an essential prerequisite for exchange across the blood-brain barrier. The metabolic changes which then ensued were quite rapid, for within 2 min after injection of [14C]glutamic acid, the glutamic acid, gluta-EXPERIMENTAL Material. Uniformly labelled ["Clglutamic acid (1 1 pclpmole) and uniformly labelled [W]aspartic acid (5 pc/pmole) were obtained from Nuclear Chicago Corp. Uniformly labelled [*'C]glutamine (0.93 pc/pmole) was obtained from Merck and Co. of Canada. The purity of the labelled compounds was tested by column and paper chromatography. Animal and organ preparations Intracisterml injection of rat. Sprague-Dawley rats approximately 100 g in weight were used. Under light ether anaesthesia 0.02 ml of a neutralized amino acid solution was injected in the midline The abhreviations used are: GSH, glutathione; GABA, y-aminobutyric acid; TCA, trichloroacetic acid

Glutamate dehydrogenase (GDH) activity was measured in leukocytes from 88 patients with various types of degenerative neurological disorders affecting primarily the cerebellum and/or the basal ganglia, and 26 healthy control subjects. Twelve patients with slowly progressive multiple-system atrophic disorders were found to have a partial deficiency of this enzyme (52% of control level). The majority of these patients evidenced a constellation of neurological findings consistent with the diagnosis of olivopontocerebellar atrophy, although others were atypical in their neurological manifestations. Thus, GDH-deficient patients were encountered with predominantly extrapyramidal manifestations (atypical Parkinson's disease), cerebellar dysfunction with peripheral neuropathy, or anterior horn cell signs, suggesting that a pleomorphic phenotypic expression of the enzymatic deficiency may occur. Seven cases of GDH deficiency were familial and 5 were sporadic. The former patient group consisted of siblings of either sex, but no parents or offspring were affected. The genetic pattern of the disorder is compatible with autosomal recessive inheritance. Patients with dominantly inherited olivopontocerebellar atrophy or other types of cerebellar or basal ganglia degenerative neurological disorders showed normal GDH activity. Leukocyte GDH was fractionated into "particulate-heat labile" and "soluble-heat stable" components. In the patients the decrease in activity was limited to the "particulate-heat labile" component. A genetic mutation of a GDH "isoenzyme" may occur in some patients with multiple-system degeneration.

In patients with recessive, adult-onset olivopontocerebellar degeneration associated with a partial deficiency of glutamate dehydrogenase, the concentration of glutamate in plasma was significantly higher than that in controls. Plasma alpha-ketoglutarate was significantly lower. Oral administration of monosodium glutamate resulted in excessive accumulation of this amino acid in plasma and lack of increase in the ratio of plasma lactate to pyruvate in the glutamate dehydrogenase-deficient patients. Decreased glutamate catabolism may result in an excess of glutamate in the nervous system and cause neuronal degeneration.

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The effect of the excitotoxin kainic acid on glutamate and glutamine metabolism was studied in cerebellar slices incubated with D-[2-14C]glucose, [U-14C]gamma-aminobutyric acid, [3H]acetate, [U-14C]glutamate, and [U-14C]glutamine as precursors. Kainic acid (1 mM) strongly inhibited the labeling of glutamine relative to that of glutamate from all precursors except [2-14C]glucose and [U-14C]glutamine. Kainic acid did not inhibit glutamine synthetase directly. The data indicate that in the cerebellum kainic acid inhibits the synthesis of glutamine from the small pool of glutamate that is thought to be associated with glial cells. Kainic acid also markedly stimulated the efflux of glutamate from cerebellar slices and this release was not sensitive to tetrodotoxin. Kainic acid stimulated efflux of both glucose- and acetate-labeled glutamate. In contrast, veratridine released glucose-labeled glutamate preferentially via a tetrodotoxin-sensitive mechanism. Kainic acid did not release [U-14C]glutamate from synaptosomal fractions. These results suggest that the bulk of the glutamate released from cerebellar slices by kainic acid comes from nonsynaptic pools.

1. The effect of fluoroacetate and fluorocitrate on the compartmentation of the glutamate-glutamine system was studied in brain slices with l-[U-(14)C]glutamate, l-[U-(14)C]aspartate, [1-(14)C]acetate and gamma-amino[1-(14)C]butyrate as precursors and in homogenates of brain tissue with [1-(14)C]acetate. The effect of fluoroacetate was also studied in vivo in mouse brain with [1-(14)C]acetate as precursor. 2. Fluoroacetate and fluorocitrate inhibit the labelling of glutamine from all precursors but affect the labelling of glutamate to a much lesser extent. This effect is not due to inhibition of glutamine synthetase. It is interpreted as being due to selective inhibition of the metabolism of a small pool of glutamate that preferentially labels glutamine.