NEURONAL DEATH AND NEUROTROPHIN GENE-EXPRESSION - LONG-LASTING STIMULATION OF NEUROTROPHIN-3 MESSENGER-RNA IN THE DEGENERATING CA1 AND CA4 PYRAMIDAL CELL-LAYERS

Neurotrophin-3 has been characterized as the product of a gene cloned by homology with nerve growth factor and brain-derived neurotrophic factor. Recombinant neurotrophin-3, like nerve growth factor and brain-derived neurotrophic factor, has been shown to enhance survival and differentiation of specific neuronal populations in vitro.4,10,15 However, little is known about its function and regulation in vivo. Both brain-derived neurotrophic factor and nerve growth factor messenger RNAs increased in adult rat brain, in a wide range of excitatory paradigms.1,3,11,13,22,28 In contrast, neurotrophin-3 messenger RNA decreased in some of them.13,22 Neurotrophin-3 is the most highly expressed neurotrophic factor in immature areas of the central nervous system. However, no stimulation of its expression in the mature central nervous system, either in physiological or pathological conditions, has been described to date. This behaviour suggests that neurotrophin-3 could be involved in biological roles different from the prototypes nerve growth factor and brain-derived neurotrophic factor. Excitatory amino acid receptor-mediated neurotoxicity (excitotoxicity) is believed to contribute to neuronal loss in a wide range of neurodegenerative conditions (for a review, see Ref. 17). Moreover, locally increased levels of the endogenous excitotoxin quinolinic acid may be involved in the natural development of neurodegenerative diseases.12,23,24 The unilateral intrahippocampal injection of 120 nmol of quinolinic acid induced seizures together with local neurodegeneration in specific cell layers. In situ hybridization histochemistry was used to analyse the spatiotemporal pattern of expression of neurotrophin-3. As in other excitotoxic paradigms, neurotrophin-3 messenger RNA clearly decreased, nearly disappearing, in the contralateral hippocampus. In contrast, a long-lasting specific stimulation of this messenger RNA expression was observed in ipsilateral CA1 and CA4 locally degenerating cell layers. The present results (i) are the first example of an increased expression of neurotrophin-3 messenger RNA in the adult brain, and (ii) suggest the involvement of this neurotrophic factor in the quinolinic acid-mediated neurodegeneration process.