Neurotrophins induce short-term and long-term changes of cortical neurotrophin expression

Neuronal activity, hormones, transmitters, physical exercise and enrichment influence cortical neurotrophin expression. Neurotrophins then elicit structural and physiological changes, and regulate gene expression. This prompted the hypothesis that neurotrophins themselves are involved in regulating neurotrophin expression. Here we investigated the mRNA expression level of brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), NT-3 and nerve growth factor (NGF) as well as the tyrosine receptor kinases TrkB and TrkC receptor in response to BDNF, NT-4, NT-3 and NGF pulses in organotypic cortex cultures. Single neurotrophin pulses evoked a dramatic up- or down-regulation of some, but not all four, neurotrophin mRNAs, even within 3-24 h, indicating an immediate impact on neurotrophin transcription. Most strikingly, neurotrophin pulses during the first 10 days in vitro (DIV) potentiated the expression of some neurotrophin mRNAs at 20 DIV, suggesting that early trophic factor experience influences the expression levels seen later in development. The NT-3 mRNA expression, for example, was consistently promoted by NGF and BDNF, suggesting that these two factors help to maintain the low level of NT-3 found in adult cortex. Rapid bidirectional changes characterized the NT-4 mRNA expression. A single pulse of NT-4 transiently increased NT-4 mRNA, whereas a BDNF pulse transiently reduced NT-4 mRNA. Surprisingly, NGF strongly potentiated BDNF mRNA and in particular NT-4 mRNA. By contrast, TrkB mRNA remained constant at ages or time points at which other mRNAs amplified from the very same cDNA libraries revealed dramatic increases or decreases. Our study suggests the existence of a complex regulatory neurotrophin network controlling the expression of other neurotrophins.