DIFFERENTIAL EXPRESSION OF P140(TRK), P75(NGFR) AND GROWTH-ASSOCIATEDPHOSPHOPROTEIN-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 on e of the major determinants of central nervous system neuronal degener ation. In order to obtain further insight into early neuronal response s to injury, lesion-induced alterations in the expression of high- and low-affinity nerve growth factor receptors, as well as growth-associa ted phosphoprotein-43 genes in nucleus basalis magnocellularis, thalam ic and neocortical neurons were studied. For this purpose, unilateral cortical devascularization operations were conducted on adult rats. An imals 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 pr obes 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 ipsilate ral to the lesion, p140(trk) gene expression significantly decreased o n days 3 and 7, while p75(NGFR) messenger RNA initially increased on d ay 3 and decreased on days 7 and 15 after lesion. GAP-43 messenger RNA levels were significantly increased in the nucleus basalis magnocellu laris 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 remai ning 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 th e 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 trea ted with nerve growth factor. Nerve growth factor treatment did not af fect the expression of growth-associated phosphoprotein-43 messenger R NA in any of the areas studied. p140(trk) messenger RNA was not up-reg ulated during the time that nerve growth factor was applied, as observ ed for p75(NGFR), but only eight days after interrupting nerve growth factor treatment. Three cell types, nucleus basalis magnocellularis, c ortical pyramidal and thalamic neurons, were probably affected in diff erent ways by the devascularization with respect to lesion extent. Con sequently, 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. Furth ermore, our results are consistent with the concept that growth-associ ated phosphoprotein-43 is regulated by target-derived factors other th an nerve growth factor and that the increase in p75(NGFR) messenger RN A in lesioned animals may occur as a consequence of increased neurotro phin activity.