Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system

This review primarily discusses work that has been performed in our laborat ories and that of our direct collaborators and therefore does not represent an exhaustive review of the current literature. Our aim is to further disc uss the role that gene expression plays in neuronal plasticity and patholog y. In the first part of this review we examine activity-dependent changes in t he expression of inducible transcription factors (ITFs) and neurotrophins w ith long-term potentiation (LTP) and kindling. This work has identified par ticular ITFs (Krox-20 and Krox-24) and neurotrophin systems (particularly t he brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase-B, Trk -B system) that may be involved in stabilizing long-lasting LTP (i.e. LTP3) . We also show that changes in the expression of other ITFs (Fos, Jun-D and K rox-20) and the BDNF/trkB neurotrophin system may play a central role in th e development of hippocampal kindling, an animal model of human temporal lo be epilepsy. In the next part of this review we examine changes in gene expression after neuronal injuries (ischemia prolonged seizure activity and focal brain inj ury) and after nerve transection (axotomy). We identify apoptosis-related g enes (p53, c-Jun, Bar) whose delayed expression selectively increases in de generating neurons, further suggesting that some forms of neuronal death ma y involve apoptosis. Moreover, since overexpression of the tumour-suppressor gene p53 induces ap optosis in a wide variety of dividing cell types we speculate that it may p erform the same Function in post-mitotic neurons following brain injuries. Additionally, we show that neuronal injury is associated with rapid, transi ent, activity-dependent expression of neurotrophins (BDNF and activinA) in neurons, contrasting with a delayed and more persistent injury-induced expr ession of certain growth factors (IGF-I and TGF beta) in glia. In this sect ion we also describe results linking ITFs and neurotrophic factor expressio n. Firstly, we show that while BDNF and trkB are induced as immediate-early genes following injury, the injury-induced expression of activinA and trkC may be regulated by ITFs. We also discuss whether loss of retrograde transport of neurotrophic factor s such as nerve growth factor following nerve transection triggers the sele ctive and prolonged expression of c-Jun in axotomized neurons and whether c -Jun is responsible for regeneration or degeneration of these axotomized ne urons. In the last section we further examine the role that gene expression may pl ay in memory formation, epileptogenesis and neuronal degeneration, lastly s peculating whether the expression of various growth factors after brain inj ury represents an endogenous neuroprotective response of the brain to injur y. Here we discuss our results which show that pharmacological enhancement of this response with exogenous application of IGF-1 or TGF-beta reduces neuro nal loss after brain injury. (C) 1999 Elsevier Science Ltd. All rights rese rved.