Upstream eventBDNF, Reduced
Down Regulation, K-Cl co-transporter 2 (KCC2)
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
BDNF is a trophic factor that has been identified to be a potent modulator of K+ Cl- co-transporter 2 (KCC2) functional expression in the brain. The up-regulation of KCC2 that is a major milestone in brain development has been shown to be actively regulated by the up-regulation of BDNF at the same period (Medina et al., 2014).
Evidence Supporting this KER
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.
Uncertainties and Inconsistencies
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.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Aguado F, Carmona MA, Pozas E, Aguiló A, Martínez-Guijarro FJ, Alcantara S, Borrell V, Yuste R, Ibañez CF, SorianoE. (2003). BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl–co-transporter KCC2. Development 130:1267-1280.
Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P, Cattaert D, Delpire E, Marsala M, Vinay L. (2010). Downregulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16:302–307.
Carmona MA, Pozas E, Martínez A, Espinosa-Parrilla JF, Soriano E, Aguado F. (2006). Age-dependent spontaneous hyperexcitability and impairment of GABAergic function in the hippocampus of mice lacking trkB. Cereb Cortex 16:47– 63.
Farrant M, Kaila K. (2007). The cellular, molecular and ionic basis of GABA(A) receptor signalling. Prog Brain Res 160:59–87.
Feller MB. (1999). Spontaneous correlated activity in developing neural circuits. Neuron 22: 653-656.
Ferrini F, DeKoninck Y. (2013). Microglia control neuronal network excitability via BDNF signalling. Neural Plast 429815.
Ganguly K, Schinder AF, Wong ST, Poo M.(2001). GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell 105:521–532.
Kafitz KW, Rose CR, Thoenen H, Konnerth A.(1999). Neurotrophin-evoked rapid excitation through trkB receptors. Nature 401:918–921.
Ludwig A, Uvarov P, Soni S, Thomas-Crusells J, Airaksinen MS, Rivera C. (2011a). Early growth response 4 mediates BDNF induction of potassium chloride co-transporter 2 transcription. J Neurosci 31:644-649.
Ludwig A, Uvarov P, Pellegrino C, Thomas-Crusells J, Schuchmann S, Saarma M, Airaksinen MS, Rivera C. (2011b). Neurturin evokes MAPK dependent up-regulation of Egr4 and KCC2 in developing neurons. Neural Plast 1-8.
Medina I, Friedel P, Rivera C, Kahle KT, Kourdougli N, Uvarov P, Pellegrino C. (2014) Current view on the functional regulation of the neuronal K+/Cl− cotransporter KCC2. Front Cell Neurosci 8: 27. O’Donovan MJ. (1999). The origin of spontaneous activity in developing networks of the vertebrate nervous system. Curr Opin Neurobiol 9:94–104.
Puskarjov M, Ahmad F, Khirug S, Sivakumaran S, Kaila K. (2014). BDNF is required for seizure-induced but not developmental up-regulation of KCC2 in the neonatal hippocampus. (2014). Neuropharmacology 1-7.
Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K. (1999). The K-/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–255.
Rivera C, Li H, Thomas-Crusells J, Lahtinen H, Viitanen T, Nanobashvili A, Kokaia Z, Airaksinen MS, Voipio J, Kaila K, Saarma M. (2002). BDNF induced TrkB activation down-regulates the K--Cl- co-transporter KCC2 and impairs neuronal Cl- extrusion. J Cell Biol 159:747–752.
Rivera C, Voipio J, Thomas-Crusells J, Li H, Emri Z, Sipila¨ S, Payne JA, Minichiello L, Saarma M, Kaila K. (2004). Mechanism of activity dependent downregulation of the neuron-specific K-Cl cotransporter KCC2. J Neurosci 24:4683– 4691.
Yeo M, Berglund K, Augustine G, Liedtke W. (2009). Novel repression of Kcc2 transcription by REST-RE-1 controls developmental switch in neuronal chloride. J Neurosci 29:14652–14662.