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Relationship: 870

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

BDNF, Reduced leads to GABAergic interneurons, Decreased

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

BDNF, Reduced

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

GABAergic interneurons, Decreased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment	adjacent	Moderate	Low	Arthur Author (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Mixed	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
During brain development	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

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 (BDNF^Met/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 BDNF^Met/Metmice 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

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

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.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Empirical evidence comes from work with laboratory rodents (rats and mice). No data are available for other species.

References

List of the literature that was cited for this KER description. More help

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.

Arenas E, Akerud P, Wong V, Boylan C, Persson H, Lindsay RM, Altar CA. (1996). Effects of BDNF and NT-4/5 on striatonigral neuropeptides or nigral GABA neurons in vivo. Eur J Neurosci. 8(8):1707–1717.

Ben-Ari Y, Khalilov I, Represa A, Gozlan H. (2004). Interneurons set the tune of developing networks. Trends Neurosci 27: 422–427.

Berghuis P, Dobszay MB, Sousa KM, Schulte G, Mager PP, Hartig W, Gorcs TJ, Zilberter Y, Ernfors P, Harkany T. (2004). Brain derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast-spiking GABAergic interneurons. Eur J Neurosci 20:1290–1306.

Blaesse P, Airaksinen MS, Rivera C, Kaila K. (2009). Cation chloride co-transporters and neuronal function. Neuron 61:820–838

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.

Cellerino A, Maffei L, Domenici L. (1996). The distribution of brain-derived neurotrophic factor and its receptor trkB in parvalbumin-containing neurons of the rat visual cortex. Eur J Neurosci 8:1190–1197.

Chakraborty G, Magagna-Poveda A, Parratt C, Umans JG, MacLusky NJ, Scharfman HE. (2012). Reduced hippocampal brain-derived neurotrophic factor (BDNF) in neonatal rats after prenatal exposure to propylthiouracil (PTU). Endocrinology 153:1311–1316.

Chen YW, Surgent O, Rana BS, Lee F, Aoki C. (2016). Variant BDNF-Val66Met Polymorphism is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia. Cereb Cortex. Aug 30.

Cherubini E, Griguoli M, Safiulina V, Lagostena L. (2011). The depolarizing action of GABA controls early network activity in the developing hippocampus. Mol Neurobiol. 43:97-106.

Danglot L, Triller A, Marty S. (2006). The development of hippocampal interneurons in rodents. Hippocampus. 16:1032-1060.

Feller MB. (1999). Spontaneous correlated activity in developing neural circuits. Neuron 22: 653-656.

Fiumelli H, Kiraly M, Ambrus A, Magistretti PJ, Martin JL. (2000). Opposite regulation of calbindin and calretinin expression by brain-derived neurotrophic factor in cortical neurons. J Neurochem. 74(5):1870–1877.

Gorba T, Wahle P. (1999). Expression of TrkB and TrkC but not BDNF mRNA in neurochemically identified interneurons in rat visual cortex in vivo and in organotypic cultures. Eur J Neurosci 11:1179–90.

Hu Y, Russek SJ. (2008). BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem. 105:1-17.

Huang ZJ. (2009). Activity-dependent development of inhibitory synapses and innervation pattern: roleof GABA signalling and beyond. J.Physiol. 587: 1881–1888.

Huang ZJ, DiCristo G, Ango F. (2007). Development of GABA innervation in the cerebral and cerebellar cortices. Nat.Rev.Neurosci. 8: 673–686.

Jin X, Hu H, Mathers PH, Agmon A. (2003). Brain-derived neurotrophic factor mediates activity-dependent dendritic growth in nonpyramidal neocortical interneurons in developing organotypic cultures. J Neurosci 23:5662–5673.

Jones KR, Farinas I, Backus C, Reichardt LF. (1994). Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell. 76(6):989–999.

Kafitz KW, Rose CR, Thoenen H, Konnerth A. (1999). Neurotrophin-evoked rapid excitation through trkB receptors. Nature 401:918–921.

Kelsom C, Lu W. (2013). Development and specification of GABAergic cortical interneurons. Cell Biosci. Apr 23;3(1):19.

Kohara K, Kitamura A, Adachi N, Nishida M, Itami C, Nakamura S, et al. (2003). Inhibitory but not excitatory cortical neurons require presynaptic brain-derived neurotrophic factor for dendritic development, as revealed by chimera cell culture. J Neurosci 23: 6123–6131.

Koibuchi N, Yamaoka S, Chin WW. (2001). Effect of altered thyroid status on neurotrophin gene expression during postnatal development of the mouse cerebellum. Thyroid 11:205–210.

Koibuchi N, Fukuda H, Chin WW. (1999). Promoter-specific regulation of the brain-derived neurotrophic factor gene by thyroid hormone in the developing rat cerebellum. Endocrinology 140: 3955–3961.

Kong S, Cheng Z, Liu J, Wang Y. (2014). Downregulated GABA and BDNF-TrkB pathway in chronic cyclothiazide seizure model. Neural Plast. 2014:310146.

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.

Marty S, Berninger B, Carroll P, Thoenen H. (1996). GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor. Neuron 16:565–570.

Marty S, Wehrle R, Sotelo C. (2000). Neuronal activity and brain-derived neurotrophic factor regulate the density of inhibitory synapses in organotypic slice cultures of postnatal hippocampus. J Neurosci 20: 8087–8095.

O’Donovan MJ. (1999). The origin of spontaneous activity in developing networks of the vertebrate nervous system. Curr Opin Neurobiol 9:94–104.

Palizvan MR, Sohya K, Kohara K, Maruyama A, Yasuda H, Kimura F, et al. (2004). Brain-derived neurotrophic factor increases inhibitory synapses, revealed in solitary neurons cultured from rat visual cortex. Neurosci 126: 955–966.

Patz S, Grabert J, Gorba T, Wirth MJ, Wahle P. (2004). Parvalbumin expression in visual cortical interneurons depends on neuronal activity and TrkB ligands during an early period of postnatal development. Cereb Cortex 14:342–51.

Polleux F, Whitford KL, Dijkhuizen PA, Vitalis T, Ghosh A. (2002). Control of cortical interneuron migration by neurotrophins and PI3-kinase signaling. Development 129:3147–60.

Puskarjov M, Ahmad F, Khirug S, Sivakumaran S, Kaila K. (2015). BDNF is required for seizure-induced but not developmental up-regulation of KCC2 in the neonatal hippocampus. Neuropharmacology. Jan;88:103-9.

Rico B, Xu B, Reichardt LF. (2002). TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat Neurosci 5:225–233.

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.

Seil FJ, Drake-Baumann R. (2000). TrkB receptor ligands promote activity-dependent inhibitory synaptogenesis. J Neurosci 20: 5367–73.

Shulga A, Blaesse A, Kysenius K, Huttunen HJ, Tanhuanpää K, Saarma M, Rivera C. (2009). Thyroxin regulates BDNF expression to promote survival of injured neurons. Mol Cell Neurosci. 42:408-418.

Shulga A, Rivera C. (2013). Interplay between thyroxin, BDNF and GABA in injured neurons. Neurosci. 239: 241-252.

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Wake, H., Watanabe, M., Moorhouse, A.J., Kanematsu, T., Horibe, S., Matsukawa, N., Asai, K., Ojika, K., Hirata, M. & Nabekura, J. (2007). Early changes in KCC2 phosphorylation in response to neuronal stress result in functional downregulation. J. Neurosci., 27, 1642–1650.

Westerholz S, de Lima AD, Voigt T. (2013). Thyroid hormone-dependent development of early cortical networks: temporal specificity and the contribution of trkB and mTOR pathways. Front Cell Neurosci 7:121.

Woo NH, Lu B. (2006). Regulation of Cortical Interneurons by neurotrophins: from development to cognitive disorders. Neuroscientist. 12: 43-56.

Yamada MK, Nakanishi K, Ohba S, Nakamura T, Ikegaya Y, Nishiyama N, et al. (2002). Brain-derived neurotrophic factor promotes the maturation of GABAergic mechanisms in cultured hippocampal neurons. J Neurosci 22:7580–5.

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.