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Glutathione as a neurotransmitter in primary visual cortex : binding sites and neuronal uptake Bowlsby, Stephen


Understanding the response properties and plasticity of primary visual (striate) cortex depends on the determination of its "chemical circuitry", yet the neurotransmitters that mediate sensory input to striate cortex are not known, and such evidence as exists is contradictory. The geniculpstriate input bears a similarity to glutamatergic neurotransmission, but glutamate is not a good candidate in this pathway. In contrast, glutathione (GSH) has been suggested to be one of the excitatory-amino-acid neurotransmitters in cortex (Ogita and Yoneda, 1987). Criteria for the identification of a neurotransmitter include the demonstration of the presence of receptors for the substance (necessary) and the demonstration of retrograde uptake and transport of the substance (supportive). The present study attempted to characterize GSH binding sites, examine their distribution, and examine possible GSH interaction with excitatory amino acid receptors in rat and cat primary visual cortex using in-vitro radioligand methods on 20-µm-thick cortex sections. In addition, the present study used in-vivo uptake and transport of radiolabeled tracers to attempt to support the localization of GSH neurotransmission to pathways within the visual system. Saturation binding experiments using radiolabeled GSH in rat primary occipital cortex sections revealed a high-affinity site (Kd = 5.4 nM; Bmax = 235 fmol/mg protein) and a denser low-affinity site (Kd = 1.3 µM; Bmax = 1.3 pmol/mg protein) , the Kd of which is typical of excitatory amino acid receptors. Kinetic and competition experiments yielded similar Kd values. Competition studies of the low-affinity GSH binding site showed a separate site as well as binding with affinity for the neurotransmitter candidates cysteine, aspartate, and glutamate. Excitatory-amino-acid receptor subtype affinity was shown for AMPA at pH 7.4 and for NMDA at pH 6.9.. Radiolabeled GSH binding in adult rat visual cortex showed a relatively uniform distribution across all cortical layers. Binding distribution studies in cat striate cortex showed densest [³⁵S]GSH binding in layer 4, the geniculostriate input layer, from 13 days postnatal to adult. Distribution of [³⁵S]GSH binding sites also showed a distinct preference for lower layer 4 in monkey striate cortex. Microinjection of [³⁵S]GSH, [³H]GSH, and its constituent amino acids, [³H]glutamate, [³⁵S]cysteine, and [³H]glycine, into primary and secondary visual cortex in the rat produced uptake to visual-system thalamic nuclei and superior colliculus. Possible retrograde uptake to cell bodies was determined for [³H]GSH and [³⁵S]cysteine in the dorsal lateral geniculate and lateral posterior nuclei in the rat. Microinjection of [³H]GSH in cat cortical area 17 produced uptake to the dorsal lateral geniculate nucleus, but possible retrograde uptake to cell bodies could not be determined. These results support the proposition that GSH plays a role as a neurotransmitter in primary visual cortex, in particular as a geniculostriate neurotransmitter, and may take part in neurotransmission by interacting with excitatory amino acid receptors in addition to GSH receptors.

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