BDNF, Reduced leads to Down Regulation, K-Cl co-transporter 2 (KCC2)

BDNF is widely expressed in the developing CNS and one of their major roles is the control of the intrinsic activity of developing neuronal networks. Further evidence has shown that it enhances the frequency and the subsequent activity synchronization in immature neurons, a process which is closely related to network maturation (Aguado et al., 2003; Carmona et al., 2006). This assumption was further supported by the ability of BDNF to depolarize cortical neurons in culture (Kafitz et al., 1999), an effect which has been linked to the developmentally regulated spontaneous network activity (Feller, 1999; O'Donoval, 1999). The spontaneous neuronal activity early in development is also closely related to Cl-homeostasis, as the increased intracellular [Cl-] facilitates the emergence of this initial spontaneous electrical activity (Farrant et al., 2007). KCC2 is the main K+ Cl- co-transporter in the brain, while its expression is developmentally controlled (Rivera et al., 1999). It is believed to be a major regulator of [Cl-] during neuronal maturation and its up-regulation coincides with the decrease of intracellular [Cl-] levels and the subsequent hyperpolarizing potential of the developing cortical neurons (Rivera et al., 1999). It has been suggested that the developmental up-regulation of KCC2 is activity dependent and closely related to the depolarizing action of GABAAR (Gangulu et al., 2001). Taking these under consideration, it was assumed that the BDNF regulation of neuronal activity was mediated by direct or indirect modulation of KCC2 expression. More detailed mechanistic evidence of this relationship further supported the initial suggestion of developmental relationship between these two factors. Specifically, it was shown that exogenously applied BDNF to immature hippocampal neurons caused a rapid increase in KCC2 mRNA levels through the activation of KCC2 promoter by the transcription factor Egr4. In consistence with the previous studies, these effects were attenuated by specific TrkB and MAPK inhibitors (Ludwig et al., 2011). Supporting to this suggestion, other studies have shown that the developmental up-regulation of KCC2 protein was enhanced by exogenous BDNF application but only in the presence of the two Repressor Elements-1 (RE-1), which are located in the promoter of the KCC2 gene (Yeo et al., 2009). The latter results lead to the hypothesis that BDNF can indirectly regulate KCC2 enhanced transcription by inhibiting the binding of the RE-1 sites to the REST transcriptional repressor complex, which could be a consequence of activation of the TrkB-related MAPK signalling pathway, as already discussed. However, the hypothesis is still under development and further investigation is required.

BDNF is a potent regulator of KCC2 not only during the developmental phase but also in the adult stage but in a different way, showing the maturation-dependent action of BDNF on KCC2 regulation (Ferrini and Konick, 2013). BDNF in mature neurons causes down-regulation of KCC2 in mRNA and protein level (Rivera et al., 2002; 2004). Other studies also suggest that BDNF up-regulates KCC2 after neuronal injury (Boulenguez et al., 2010) and after seizures (Puskarjov et al., 2014) and the suggested plausible reason is that the repairing procedure of the neurons demands properties similar to those of the immature neurons. Up to date, the exact mechanistic pathways that are followed in the different abovementioned cases are not well characterized and understood. In the most recent study of Puskarjov et al., 2014, BDNF-/- mice were utilized to show that in the absence of BDNF the seizure-induced up regulation of KCC2 was eliminated, but interestingly no change in early (P5-6) or later (P13-14) postnatal KCC2 expression was observed compared to the wild type littermates. However, the functionality of the protein was not investigated nor the ability of the neurons to extrude Cl- in the absence of BDNF. Additionally, other studies have shown that the up-regulation of KCC2 via the transcriptional factor Egr4 is also regulated by a different neurotrophic factor, the neurturin (Ludwig et al., 2011b). These results reveal that the same transcriptional pathways are downstream from different neurotrophic factors and they might lead to the same outcome under different conditions. This suggestion should be further investigated, as this could explain the compensation mechanisms that are activated in the total absence of BDNF, and which might be different from those that are triggered by the decrease of BDNF levels.