INCREASED EXPRESSION OF TRKB AND TRKC MESSENGER-RNAS IN THE RAT FOREBRAIN AFTER FOCAL MECHANICAL INJURY

Tyrosine protein kinases trkA, trkB and trkC are signal transduction r eceptors for a family of neurotrophic factors known as the neurotrophi ns. Here we report on changes in the expression of messenger RNAs for trkA, trkB and trkC in the brain following an injury caused by inserti on of a 30-gauge needle into adult rat hippocampus or neocortex. Quant itative in situ hybridization revealed no change in the level of trkA messenger RNAs in any brain region following this insult. In contrast, increased levels of trkB messenger RNA compared to untreated animals were seen in the granule cell layer of the dentate gyrus ipsilateral t o the injury already 30 min after the injury. The increase reached max imal levels (four-fold) between 2 and 4 h, but returned to control lev els 8 h after the injury. No change was seen in the contralateral dent ate gyrus. The levels of trkC messenger RNA increased in the same brai n regions as trkB messenger RNA, though with a delayed response, reach ing a maximal increase of 3.3-fold 4 h after the injury. As for trkB m essenger RNA, the level of trkC messenger RNA then tapered off and rea ched control levels 8 h after the injury. However, 4h after the injury , a 1.7-fold increase of trkB and trkC messenger RNAs were seen in the ipsilateral piriform cortex. The increases of trkB and trkC messenger RNAs were confirmed using a nuclease protection assay. Increases of b oth trkB and trkC messenger RNAs were also seen in the piriform cortex , but not in the hippocampus, following needle insertion into the neoc ortex. Pretreatment of the animals with the non-competitive N-methyl-D -aspartate antagonist ketamine completely prevented the increases of t rkB arid trkC messenger RNAs, suggesting that the brain injury caused a release of glutamate with subsequent activation of iv-methyl-D-aspar tate receptors. In contrast, the anticonvulsive drug diazepam, the mus carinic antagonist atropine and the calcium-channel antagonist nimodip ine had no effect on the increases of trkB and trkC messenger RNAs. Co mbined with previous data on the expression of neurotrophin messenger RNAs following similar injuries, our results support the hypothesis th at increased levels of neurotrophins and their receptors could protect against neuronal damage following a brain insult.