Noradrenergic stimulation of BDNF synthesis in astrocytes: Mediation via alpha(1)- and beta(1)/beta(2)-adrenergic receptors

Brain-derived neurotrophic factor (BDNF) synthesis in astrocytes induced by noradrenaline (NA) is a receptor-mediated process utilizing two parallel adrenergic pathways: beta(1)/beta(2)-adrenergic/cAMP and the novel alpha(1)-adrenergic/PKC pathway. BDNF is produced by astrocytes, in addition to neurons, and the noradrenergic system plays a role in controlling BDNF synthesis. Since astrocytes express various subtypes of alpha- and beta-adrenergic receptors that have the potential to be activated by synaptically released NA, we focused our present study on the mediatory role of adrenergic receptors in the noradrenergic up-regulation of BDNF synthesis in cultured neonatal rat cortical astrocytes. NA (1 mu M) elevates BDNF levels by four-fold after 6 h of incubation. Its stimulation was partly inhibited by either the beta(1)-adrenergic antagonist atenolol, the beta(2)-adrenergic antagonist ICI 118,55 1, or by the alpha(1)-adrenergic antagonist prazosin, while the alpha(2)-adrenergic antagonist yohimbine showed no effect. BDNF levels in astrocytes were increased by the specific beta(1)-adrenergic agonist dobutamine and the beta(2)-adrenergic agonist salbutamol, as well as by adenylate cyclase activation (by forskolin) and PKA activation (by dBcAMP). However, none of the tested agonists or mediators of the intracellular beta-adrenergic pathways were able to reach the level of NA's stimulatory effect. BDNF cellular levels were also elevated by the alpha(1)-adrenergic agonist methoxamine, but not by the alpha(2)-adrenergic agonist clonidine. The increase in intracellular Ca2+ by ionophore A23187 showed no effect, whereas PKC activation by phorbol 12-myristate 13-acetate (TPA) potently stimulated BDNF levels in the cells. The methoxamine-stimulated BDNF synthesis was inhibited by desensitizing pretreatment with TPA, indicating that the alpha(1)-stimulation was mediated via PKC activation. In conclusion, the synthesis of astrocytic BDNF stimulated by noradrenergic neuronal activity is an adaptable process using multiple types (alpha(1) and beta(1)/beta(2)) of adrenergic receptor activation. (C) 2007 Elsevier Ltd. All rights reserved.