RESUMEN
D-Serine is an endogenous agonist of NMDA receptors that occurs in astrocytes in gray matter areas of the brain. D-Serine is synthesized from L-serine by the activity of a glial enriched serine racemase, but little is known on the properties of D-serine transport and factors regulating its synaptic concentration. In the present report we characterize the transport of D-serine in astrocytes. In primary astrocyte cultures, D-serine uptake is dependent on sodium ions and exhibits both low affinity and low specificity for D-serine. The kinetics of D-serine transport resembles that of ASCT type transporters as several small neutral amino acids strongly inhibit the uptake of D-serine. D-Serine fluxes are coupled to counter-movement of L-serine and to a less extent to other small neutral amino acids. Thus, addition of D-serine to cell cultures elicits robust efflux of intracellular L-serine. Conversely, physiological concentrations of L-serine induce efflux of preloaded D-serine from astrocytes. L-Serine was more effective than kainate, which have been previously shown to induce D-serine release from astrocytes upon stimulation of non-NMDA type of glutamate receptors. The features of D-serine transport we describe reveal possible new mechanisms controlling the synaptic concentration of D-serine.
Asunto(s)
Astrocitos/metabolismo , Agonistas de Aminoácidos Excitadores/farmacocinética , Neurotransmisores/farmacocinética , Serina/farmacocinética , Aminoácidos Neutros/farmacología , Animales , Unión Competitiva , Transporte Biológico/efectos de los fármacos , Proteínas Portadoras/metabolismo , Células Cultivadas , Agonistas de Aminoácidos Excitadores/farmacología , Membranas Intracelulares/metabolismo , Iones , Cinética , Neurotransmisores/química , Neurotransmisores/farmacología , Ratas , Ratas Wistar , Serina/química , Serina/farmacología , Sodio/metabolismo , EstereoisomerismoRESUMEN
INTRODUCTION: Huntington's disease (HD) is a progressive neurodegenerative disorder, characterized by severe degeneration of basal ganglia neurons. Behavioral symptoms of HD include abnormal, uncontrollable and constant choreiform movements, impaired cognitive function and emotional disturbance. OBJECTIVE: In order to explore the changes of cognitive and motor functions induced by quinolinate lesion we realized this experiment. MATERIALS AND METHODS: We studied the behavior of rats with unilateral quinolinate induced lesions of the medial striatum. Intact 3 months old male rats (n = 23) were trained in the Morris Water Maze during three consecutive days, eight trials/day (acquisition), and before surgery they were randomly assigned either to intact or lesion groups. Fifteen days after the lesion the rats were tested using retention test (one day/four trials, with the escape platform in the same position as in acquisition test), on the next three days the rats were tested in the transfer test (three days/eight trials-day, with the platform in the new position). The Paw reaching test and the asymmetrical rotational behavior test in respond to amphetamine were also tested in these rats. RESULTS: Lesioned animals exhibited deficient retrieval of stored memories of visuospatial skills and impaired transfer of learning. In relation with motor activity the lesioned rats showed a profound impairment in the skill of the left forelimb for reaching food compared with its right forelimb as well as with the forelimb abilities of intact rats. The lesioned animals showed significant rotational behavior induced by amphetamine agonist, ipsilateral to the lesioned striatum. CONCLUSIONS: These results are consistent with the notion that the striatal degeneration could sufficiently account for the cognitive abnormalities associated with HD, and with the key role played by basal ganglia in enabling voluntary and postural adjustment of the movements.