Forskolin-induced expression of tyrosine hydroxylase in human foetal braincortex

Brain-derived neurotrophic factor (BDNF) has previously been shown by this and other laboratories to work in concert with dopamine (DA) to induce the dopaminergic phenotype in foetal rat and human cerebral cortex during speci fied sensitive developmental stages. In the present study this induction by BDNF/DA was found to be greatly amplified by adding forskolin(fsk: 10 mu M ) to the rat and human cerebral cortex cultures together with DA (10 mu M) and BDNF (50 ng/ml). This amplification was 14-fold for human tissue and 2- fold for rat tissue treated over an 80% shorter period. Compared to treatme nt with BDNF alone, the additional fsk increased tyrosine hydroxylase-posit ive (TH+) cell numbers by 220-fold in the human and 26-fold in the rat tiss ue. Parallel reverse transcription-polymerase chain reaction (RT-PCR) measu rement of TH mRNA showed substantial increases above control levels when BD NF/DA or BDNF/DA/fsk treatments were applied. Since fsk boosts intracellula r levels of cyclic AMP (cAMP), its amplifying action when added together wi th BDNF/DA is likely to be due to interactions via the cAMP response elemen t/cAMP response element binding protein (CRE/CREB) systems. This is discuss ed. (C) 1999 Elsevier Science B.V. All rights reserved.