Upstream eventBDNF, Reduced
GABAergic interneurons, Decreased
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment||adjacent||Moderate||Low|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
GABAergic interneurons are remarkably diverse and complex in nature and they are believed to play a key role in numerous neurodevelopmental processes (Southwell et al., 2014). Among them, those that express parvalbumin (PV) (marker of GABAergic interneurons) as their calcium-binding protein are the ones subjected to regulations by neurotrophins and BDNF specifically (Woo and Lu, 2006). These neurons do not express the BDNF protein but its functional receptor, Trk-B (Cellerino et al., 1996; Marty et al., 1996; Gorba and Wahle, 1999). BDNF is released by the BDNF-producing neurons of the CNS and binds to Trk-B of the GABA PV-interneurons, an interaction necessary for the subsequent developmental effects mediated by BDNF (Polleux et al., 2002; Jin et al., 2003; Rico et al., 2002; Aguado et al., 2003). BDNF promotes the morphological and neurochemical maturation of hippocampal and neocortical interneurons and promotes GABAergic synaptogenesis (Danglot et al., 2006 and Hu and Russek, 2008). BDNF also regulates the expression of the GABA-specific K(+)/Cl(-) co-transporter, KCC2, which is responsible for switching of GABA action from excitatory to inhibitory, and consequently determines the nature of GABA-induced development of glutamatergic (excitatory) synapses (Wang and Kriegstein, 2009; Blaesse et al., 2009).
Evidence Supporting this KER
Proper function of the Central Nervous System (CNS) results from the closely regulated development and function of the different neuronal subtypes and is driven by the overall balance between excitation and inhibition. In the cerebral cortex the synaptic inhibition is mediated by the GABAergic interneurons, which regulate also the neuronal developmental excitability and thereby the function and maturation of the neuronal networks (Voigt et al., 2001; Cherubini et al., 2011).
Many trophic factors are implicated in the regulation of these processes but among them BDNF stands out as the prime candidate due to do its effects on interneuron development (Palizvan et al., 2004; Patz et al., 2004; Woo and Lu, 2006; Huang et al., 2007; Huang, 2009). Exogenous application of BDNF in developing neocortical and hippocampal GABAergic interneurons has demonstrated an enhanced dendritic elongation and branching in cultures (Jin et al., 2003; Vicario-Abejon et al., 1998). Interneuron differentiation was also affected by endogenous BDNF, as the length and branching of GABAergic interneurons (GFP-positive (i.e., BDNF+/+)), was promoted only when they were innervated by BDNF-releasing interneurons (Kohara et al., 2003). Due to these dendritic effects of BDNF on GABAergic interneurons, this neurotrophin was suggested to promote also the formation of inhibitory synapses, which was further supported by several in vitro studies. Exogenous application of BDNF significantly increased the number of functional synapses in culture (Vicario-Abejon et al., 1998; Marty et al., 2000), while blocking BDNF with antibodies greatly reduced the formation of inhibitory synapses (Seil and Drake-Baumann, 2000). Similar results were observed in vivo in transgenic mice with deleted Trk-B gene in cerebellar precursors, in which Trk-B receptor was found to be the prerequisite for inhibitory synapses formation (Rico et al., 2002). Additionally, BDNF was reported to elicit presynaptic changes in GABAergic interneurons, as several presynaptic proteins were up-regulated after BDNF application (Yamada et al., 2002; Berghuis et al., 2004). A significant increase of GABAA receptor density was observed in cultured hippocampus-derived neurons after treatment with BDNF (Yamada et al., 2002).
BDNF is also a potent regulator of spontaneous neuronal activity (Aguado et al., 2003; Carmona et al., 2006), a major milestone of the developing hippocampus and an important feature of the CNS. Further supporting studies have shown that it has the ability 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'Donovan, 1999).
The spontaneous neuronal activity early in development is also closely related to Cl-homeostasis, which is developmentally regulated by KCC2, the main K+ Cl- co-transporter in the brain (Rivera et al., 1999). Because neuronal expression of KCC2 is low during early development, the intracellular [Cl-] cannot be extruded leading to the depolarizing effect of GABA during this period (Ben-Ari et al., 2004). Taking these under consideration, it was demonstrated that the effects of BDNF on neuronal activity was mediated by the KCC2 regulation, as observed in several in vitro and in vivo studies (Ludwig et al., 2011a and 2011b; Yeo et al., 2009; Aguado et al., 2003; Carmona et al., 2006).
In support to this KER, recent studies have demonstrated that injured hippocampal neurons can survive and be regenerated through the same mechanism (Shulga et al., 2013). Indeed, after mature nerve injury, KCC2 is down-regulated and the GABA responses switch to depolarization, in a way similar to the early developmental stages. The rescue and re-generation of these neurons requires the switch of GABA from depolarization to hyperpolarization, a process driven by BDNF and the subsequent KCC2 up-regulation in hippocampal neurons (Shulga et al., 2009) during brain development.
It is widely accepted that BDNF expression is regulated by TH (Koibuchi et al., 1999; 2001; Chakraborty et al., 2012). Deregulation of BDNF signaling has been shown to decrease cortical GABA interneuron markers (Kelsom and Lu, 2013; Fiumelli et al., 2000; Arenas et al., 1996; Jones et al., 1994).
- Westerholz et al., 2013 In recent in vitro studies in rat T3-deficient cultures of cortical PV+ interneurons, it was shown that the number of synaptic boutons was reduced, an effect that was abolished after exogenous BDNF application. Additionally, inhibition of BDNF by K252a (a TrK antagonist) in cultures containing T3 resulted also in decreased number of synaptic boutons, as in the T3-deprived cultures. These results suggest that BDNF signaling promotes the formation of synaptic boutons and that this function is mediated by TH (T3 and T4).
- Chen et al., 2016 BDNF-Val66Met knock-in mice (BDNFMet/Met) are known for reduction in the activity-dependent BDNF secretion and elevated anxiety-like behaviors. This study showed that GABAergic innervations of pyramidal neurons of BDNFMet/Met mice are reduced at distal dendrites in hippocampal CA1 and medial prefrontal cortex, compared to wild type mice.
- Kong et al., 2014 This study showed that chronic seizure rats 6 months after treatment with cyclothiazide (CTZ, a seizure inducer), underwent decrease of both GAD (from 75.2 ± 13.0 in CA1, 79.7 ± 9.7 in CA3, and 251.5 ± 4.3 in DG, respectively, to 3.0 ± 0.5 in CA1, 3.6 ± 0.9 in CA3, and 5.3 ± 1.8 in DG) and GAT-1 (from 60.7 ± 3.0 in CA1, 55.7 ± 9.1 in CA3, and 212.3 ± 11.3 in DG, respectively, to 20.7 ± 8.6 in CA1, 24.3 ± 3.4 in CA3, and 24.7 ± 13.3 in DG) across CA1, CA3, and dentate gyrus area of the hippocampus. Also, hippocampal decrease of both BDNF+ cells (from 70.7 ± 9.0 in CA1, 72.2 ± 3,7 in CA3, and 138.3 ± 15.9 in DG, respectively, to 4.1 ± 1.0 in CA1, 2.9 ± 0.1 in CA3, and 21.2 ± 16.2 in DG) and TrkB+ (BDNF receptor) cells (from 126.7 ± 7.2 in CA1, 275.7 ± 56.3 in CA3, and 399.2 ± 22.4 in DG, respectively, to 64.7 ± 16.2 in CA1, 158.3 ± 41.7 in CA3, and 250.3 ± 46.8 in DG) was observed.
- Aguado et al., 2003 BDNF overexpression in transgenic embryos raised the spontaneous activity of E18 hippocampal neurons, as shown by increased number of synapses (63% more synapses in the hippocampus of BDNF transgenic embryos than in controls), and increased spontaneous neuronal activity (2.3 times more active neurons than wild type embryos, and 36.3% greater rates of activation). Moreover, BDNF transgenic embryos had higher number of GABAergic interneuron synapses, as shown by higher GAD67 mRNA (by 3-fold) and K(+)/Cl(-) KCC2 mRNA expression (by 4.3-fold) (responsible for the conversion of GABA responses from depolarizing to inhibitory), without altering the expression of GABA and glutamate ionotropic receptors. These data indicate that BDNF controls both GABAergic pre- and postsynaptic sites.
Uncertainties and Inconsistencies
The role of BDNF on differentiation and maturation of GABAergic interneurons is supported by the studies described in Weight of Evidence section. However, in a recent publication (Puskarjov et al., 2015) 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, but neither the functionality of KCC2 protein was 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 transcription factor Egr4 is also regulated by a different neurotrophic factor, neurturin (Ludwig et al., 2011b). These results reveal that the same transcriptional pathways, such as KCC2, can be activated by different neurotrophic factors and might lead to the same outcome under different conditions. This hypothesis should be further investigated, as it 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 a decrease of BDNF levels.
Quantitative Understanding of the Linkage
There is a lack of quantitative studies linking brain BDNF levels (gene and/or protein) and the amount of GABAergic interneurons, resulting in changes of their morphology and function, therefore no robust quantitative information can be provided.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Empirical evidence comes from work with laboratory rodents (rats and mice). No data are available for other species.
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