EXPRESSION OF NEUROTROPHIN AND TRK RECEPTOR GENES IN ADULT-RATS WITH FIMBRIA TRANSECTIONS - EFFECT OF INTRAVENTRICULAR NERVE GROWTH-FACTOR AND BRAIN-DERIVED NEUROTROPHIC FACTOR ADMINISTRATION

The expression of the specific trk receptors for nerve growth factor a nd brain-derived neurotrophic factor (trkA and trkB) has been assayed by messenger RNA in situ hybridization in adult rats with partial fimb rial transections along with intraventricular treatment of nerve growt h factor or brain-derived neurotrophic factor. In the forebrain, speci fic hybridization labeling for trkA messenger RNA showed an identical pattern to that of choline acetyltransferase messenger RNA supporting the view that trkA expression is confined to the cholinergic populatio n in the basal forebrain and the cholinergic interneurons in the stria tum. After partial unilateral transections of the fimbria there was a progressive loss of choline acetyltransferase and trkA messenger RNA e xpression in the septal region ipsilateral to the lesion. Daily intrav entricular administration of brain-derived neurotrophic factor or nerv e growth factor partially prevented the lesion-induced decrease in the levels of both messengers, the latter being more effective than the f ormer. Grain count analysis of individual cells was used to test wheth er the two factors upregulated choline acetyltransferase or trkA expre ssion in individual cells surviving the lesion. Brain-derived neurotro phic factor treatment failed to induce any change in the levels of bot h messengers per neuron in the septal area. In contrast, daily intrave ntricular administration of nerve growth factor upregulated both choli ne acetyltransferase and trkA messenger RNA expression in individual n eurons. This upregulation was evident on ipsilateral and contralateral sides, suggesting that nerve growth factor is able to upregulate thes e markers in intact and injured cholinergic cells in the basal forebra in. Similar to the situation in the septum, brain-derived neurotrophic factor did not upregulate choline acetyltransferase or trkA expressio n in the striatum. However, nerve growth factor administration strongl y upregulated choline acetyltransferase messenger RNA expression by in dividual cholinergic neurons of the striatum. A medial to lateral grad ient decrease in this upregulation was detected in the striatum ipsila teral to the side of administration, suggesting a limited diffusion of the nerve growth factor protein from the ventricle into brain parench yma. In contrast to the strong effect on choline acetyltransferase exp ression, nerve growth factor treatment was ineffective in altering trk A messenger RNA in the striatum. The contrasting findings between sept um and striatum suggest different regulatory mechanisms for trkA messe nger RNA expression in the two cholinergic populations. Since nerve gr owth factor was found to upregulate the expression of its trkA recepto r, we tested whether brain-derived neurotrophic factor administration had similar effects on the regulation of its trkB receptor. Neither br ain-derived neurotrophic factor administration nor fimbrial transectio n induced any change in the expression of full-length or truncated trk B messenger RNAs. However, in situ hybridization for brain-derived neu rotrophic factor messenger RNA detected lower levels in CA2-CA3 follow ing the fimbrial transections in the ipsilateral side, which confirmed that septal cholinergic afferents are necessary for maintaining norma l levels of brain-derived neurotrophic factor messenger RNA expression in the hippocampus.