DIFFERENTIAL EXPRESSION OF P140(TRK), P75(NGFR) AND GROWTH-ASSOCIATED PHOSPHOPROTEIN-43 GENES IN NUCLEUS BASALIS MAGNOCELLULARIS, THALAMUS AND ADJACENT CORTEX FOLLOWING NEOCORTICAL INFARCTION AND NERVE GROWTH-FACTOR TREATMENT

A loss of target-derived neurotrophic factors is hypothesized to be one of the major determinants of central nervous system neuronal degeneration. In order to obtain further insight into early neuronal responses to injury, lesion-induced alterations in the expression of high- and low-affinity nerve growth factor receptors, as well as growth-associated phosphoprotein-43 genes in nucleus basalis magnocellularis, thalamic and neocortical neurons were studied. For this purpose, unilateral cortical devascularization operations were conducted on adult rats. Animals received i.c.v. infusions of vehicle or nerve growth factor (12 mu g/day) and were killed at one, three, seven and 15 days post-lesion. In situ hybridization studies using S-35-labelled oligonucleotide probes for p75(NGFR), p140(trk) and growth-associated phosphoprotein-43 messenger RNAs revealed that these genes were differentially regulated following the lesion. In the nucleus basalis magnocellularis ipsilateral to the lesion, p140(trk) gene expression significantly decreased on days 3 and 7, while p75(NGFR) messenger RNA initially increased on day 3 and decreased on days 7 and 15 after lesion. GAP-43 messenger RNA levels were significantly increased in the nucleus basalis magnocellularis on post-lesion days 3 and 7. Moreover, in contrast to p75(NGFR) or 140(trk), growth-associated phosphoprotein-43 messenger RNA levels were significantly increased in pyramidal neurons located in the remaining cortex adjacent to the cortical lesion at all time points. In the lateral and ventroposterior nuclei of the thalamus, growth-associated phosphoprotein-43 messenger RNA level was slightly increased on days 1 and 3 and was dramatically decreased, significantly below the levels in sham-operated controls, on post-lesion days 7 and 15. During nerve growth factor application, the level of p140(trk) messenger RNA in the lesioned nucleus basalis magnocellularis returned to values observed in the contralateral nucleus basalis magnocellularis while p75(NGFR) messenger RNA was increased above values noted in all animals not treated with nerve growth factor. Nerve growth factor treatment did not affect the expression of growth-associated phosphoprotein-43 messenger RNA in any of the areas studied. p140(trk) messenger RNA was not up-regulated during the time that nerve growth factor was applied, as observed for p75(NGFR), but only eight days after interrupting nerve growth factor treatment. Three cell types, nucleus basalis magnocellularis, cortical pyramidal and thalamic neurons, were probably affected in different ways by the devascularization with respect to lesion extent. Consequently, the remaining number of synaptic contacts in each of these brain areas is most likely different which may lead to a differential regulation of growth-associated phosphoprotein-43 messenger RNA. Furthermore, our results are consistent with the concept that growth-associated phosphoprotein-43 is regulated by target-derived factors other than nerve growth factor and that the increase in p75(NGFR) messenger RNA in lesioned animals may occur as a consequence of increased neurotrophin activity.