Downregulation of connexin43 potentiates noradrenaline‐induced expression of brain‐derived neurotrophic factor in primary cultured cortical astrocytes

Abstract

Decreased expression of brain‐derived neurotrophic factor (BDNF) is involved in the pathology of depressive disorders. Astrocytes produce BDNF following antidepressant treatment or stimulation of adrenergic receptors. Connexin43 (Cx43) is mainly expressed in central nervous system astrocytes and its expression is downregulated in patients with major depression. How changes in Cx43 expression affect astrocyte function, including BDNF production, is poorly understood. The current study examined the effect of Cx43 knockdown on BDNF expression in cultured cortical astrocytes after stimulation of adrenergic receptors. The expression of Cx43 in rat primary cultured cortical astrocytes was downregulated with RNA interference. Levels of messenger RNAs (mRNAs) or proteins were measured by real‐time PCR and western blotting, respectively. Knockdown of Cx43 potentiated noradrenaline (NA)‐induced expression of BDNF mRNA in cultured astrocytes. NA treatment induced proBDNF protein expression in astrocytes transfected with small interfering RNA (siRNA) targeting Cx43, but not with control siRNA. This potentiation was mediated by the Src tyrosine kinase‐extracellular signal‐regulated kinase (ERK) pathway through stimulation of adrenergic α1 and β receptors. Furthermore, the Gq/11 protein‐Src‐ERK pathway and the G‐protein coupled receptor kinase 2‐Src‐ERK pathway were involved in α1 and β adrenergic receptor‐mediated potentiation of BDNF mRNA expression, respectively. The current studies demonstrate a novel mechanism of BDNF expression in cortical astrocytes mediated by Cx43, in which downregulation of Cx43 increases, through adrenergic receptors, the expression of BDNF. The current findings indicate a potentially novel mechanism of action of antidepressants, via regulation of astrocytic Cx43 expression and subsequent BDNF expression.

The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex

“…While the involvement of noradrenergic signaling was not tested in this study (Martínez-Gallego et al, 2022), it clearly adds to the evidence that astrocytes are potent helmsmen of synaptic plasticity direction (Falcón-Moya et al, 2020;Hennes et al, 2020;Wahis et al, 2021b;Koh et al, 2022). Future studies could also explore the molecular mechanisms underlying the role of astrocytes in NA-mediated plasticity in V1, for instance by testing the involvement of potential gliotransmitters, such as ATP/Adenosine, D-Serine, GABA or BDNF (Pankratov and Lalo, 2015;Morioka et al, 2021;Liu et al, 2022;Martínez-Gallego et al, 2022). Furthermore, we believe it likely that our findings in acute slices extrapolate to the in vivo situation, based on the findings of Monai and colleagues (Monai et al, 2016).…”