Relationship:871

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
GABAergic interneurons morphology and function , Altered Synaptogenesis, Decreased

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Inhibition of Na+/I- symporter (NIS) decreases TH synthesis leading to learning and memory deficits in children Directly Leads to Strong Weak

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

Early in cortical development, the GABAergic interneurons have been found to contribute to key aspects of the brain development. A precise balance between excitatory and inhibitory drives in cortical neurons is crucial for the formation and maturation of the neuronal connections and eventually the proper neural circuitry function. In the cerebral cortex, the young neurons first receive GABAergic depolarizing inputs before forming any synapses (Owens et al., 1999; Tyzio et al., 1999; Hennou et al., 2002), and thus the GABAergic system is believed to be the main regulator of this cascade. Indeed, initial depolarizing GABAergic transmission is required for the formation of the glutamatergic synapses and is therefore responsible for the regulation of the balance between excitation and inhibition in the developing cortex (Wang and Kriegstein, 2009).

Weight of Evidence

Biological Plausibility

Early in development of the neocortex, the GABAergic interneurons are implicated in the emergence of a spontaneous synchronized activity, which has a fundamental role in the activation of glutamatergic synapses, the synchronization of synaptogenesis and the establishment of long –range cortico-cortical connections (Voigt et al., 2001; 2005). Increasing evidence suggest that GABAergic signaling is the main regulator of this early activity, as it is established before the glutamatergic one in the neocortex (Owens et al., 1999). Despite the fact that GABA is the main inhibitory neurotransmitter in the adult central nervous system, it exerts depolarizing actions in the immature brain (Ben-Ari et al., 2007), caused by the low levels of Cl- concentration in the post-synaptic cells (Rivera et al., 1999; Ehrlich et al., 1999). K-Cl co-transporter 2 (KCC2) is the main Cl- efflux mechanism with a developmentally-regulated expression profile in the brain and it is therefore thought to be the regulator of GABA signalling during the early neuronal development. The effects of KCC2 on the levels of [Cl-]I in immature neurons and the subsequent effects on the shift of the GABA signaling has been extensively studied during the last decades:

• Existing data indicate that KCC2 is sufficient to induce the end of the depolarizing and excitatory period of GABA during cortical neurons development (Lee et al., 2005; Chudotvorova et al., 2005) and to effectively decrease the [Cl-]I in immature rat neurons (Chudotvorova et al., 2005).

• Transcriptional repression of KCC2 in rat cortical neurons delayed the GABA switch corresponding to significant changes of [Cl-]I in the same neurons (Yeo et al., 2009).

On the other hand, several studies focused on the effects of GABA signaling on synaptogenesis and they all had convergent results leading to a strong biological plausibility of this relationship.

• The early shift of GABA-induced excitation to inhibition not only defects the synaptic integration, but it also results in deficient circuitry development (Wang and Kriegstein, 2008). This has been demonstrated in rodents and mammals cortical neurons in culture.

• Premature GABA switch has also morphological effects in cortical neurons, as it has been shown to drive in fewer and shorter dendrites with defective effects in synaptic formation (Cancedda et al., 2007).

• Likewise, in the adult dentate gyrus, the GABA depolarization in newborn granule cells regulates synapse formation in embryos and adults (Ge et al., 2006).

• An early hyperpolarizing shift in the Cl− reversal potential, by premature expression of KCC2, has been shown to increase the ratio of inhibitory to excitatory inputs both in Xenopus tectal neurons and rat cortical neurons in culture (Chudotvorova et al., 2005; Akerman and Cline, 2006).

The mechanistic details of this relationship are not yet known but the most possible mechanism entails the cooperation between GABA and NMDA receptor activation (Wang and Kriegstein, 2008; Cserep et al., 2012). Cortical neurons begin to express functional NMDA receptors when they migrate to the cortical plate, but these initial glutamatergic synapses are “silent” because of the Mg2+ block of NMDA receptors at the resting membrane potential (LoTurco et al., 1991; Akerman and Cline, 2006). GABAergic depolarization can facilitate relief of this voltage-dependent Mg2+ block and allow Ca2+ entry to initiate intracellular signalling cascades (Leinekugel et al., 1997). This mechanism suggests that the initial depolarizing GABAergic transmission is required for the formation of the glutamatergic synapses and is therefore responsible for the regulation of the balance between excitation and inhibition in the developing cortex (Wang and Kriegstein, 2009).

Empirical Support for Linkage

As described above, the correlation between the GABA function and synaptogenesis has been mainly studied through the developmental modifications of intracellular Cl- gradient and the subsequent GABA switch. In all available cases, this is performed by disturbing KCC2 or NKCC1 expression with genetic or mechanical manipulations of the neuronal models. In regards to toxicological studies, BPA is an environmental toxicant that it has been found to affect both KCC2 expression and the developmental chloride shift (Yeo et al., 2013):

• 100 nm of BPA causes ≥ 25% decrease of KCC2 mRNA expression and subsequent significant increase of [Cl-]I reduction rate, without eliminating the chloride shift. These changes correspond to the neuronal function of GABA.

The temporal concordance of GABA shift and synaptogenesis is extensively reviewed by Ben-Ari et al., 2007; 2012. It is widely accepted that the first spontaneous synaptic activity in the cortex is driven by the GABA-mediated depolarization and it is necessary for the subsequent synapse formation in the brain. Furthermore, the absence of thyroxin (T3) in cultures of cortical GABAergic interneurons can delay the typical developmental KCC2 up-regulation and subsequently the GABA shift, with a profound decrease in the number of synapses (Westerholz et al., 2010; 2013). These findings also concur with studies in other brain areas, such as the auditory brainstem and the hippocampus (Friauf et al., 2008; Hadjab-Lallemend et al., 2010), supporting the idea of KCC2 and GABA correlation in the brain, and their implication in synaptogenesis.

Uncertainties or Inconsistencies

In vivo evidence for the role of GABA in synaptogenesis is controversial. Ji et al., 1999 have shown that in GAD-/- double knock out mice, in which the production of GABA was reduced to less than 5%, the development of the brain until the birth was normal. These mice die at birth and therefore synaptogenesis and circuit development could not be controlled, however no developmental defects were detected in the neocortex, cerebellum and hippocampus of these animals by the time of their death. These findings suggest that GABA is not crucial for development and concur with the idea that glutamate, glycine and taurine can compensate for the lack of GABA (LoTurco et la., 1995; Flint et al., 1998).

In KCC2 knock out mice, apart from lung atelectasis, no other obvious histological changes in the brain were observed in neonatal mice (Hubner et al., 2001). However, these mice died at birth, before the GABA switch takes place, and therefore no effects on GABA switch and on subsequent synaptogenesis could be observed.

Additionally, after premature expression of KCC2 transporter an increase of the excitatory synapses was observed, but the glutamatergic synapses were not affected (Chudotvorova et al., 2005), as in the case of NKCC1 knock out mice (Wang and Kriegstein, 2008). These contradictory results reveal the complexity of the developmental brain and suggest that many different mechanisms are involved in the regulation of the temporal profile of the two main neuronal co-transporters, namely the KNCC1 and KCC2. However, in all cases the importance of Cl- homeostasis in the developmental cortex and its correlation with the proper synapse formation is demonstrated.

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Evidence Supporting Taxonomic Applicability

Most of the available studies have been performed in rodent models, referenced in the "Biological plausibility" section.

The relationship between KCC2 and GABA signalling has been also demonstrated in the retinotectal circuit of Xenopus (Akerman and Cline, 2006).

References

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Ben Ari Y, Gaiarsa JL, Tyzio R, Khazipov R. (2007). GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev 87:1215–84.

Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E. (2012). The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist. 18(5):467-486.

Cancedda L, Fiumelli H, Chen K, Poo MM. (2007). Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. J Neurosci 27: 5224–5235.

Chudotvorova I, Ivanov A, Rama S, Hubner CA, Pellegrino C, Ben-Ari Y, Medina I (2005). Early expression of KCC2 in rat hippocampal cultures augments expression of functional GABA synapses. J Physiol 566: 671–679.

Cserép C, Szabadits E, Szőnyi A, Watanabe M, Freund TF, Nyiri G. (2012). NMDA receptors in GABAergic synapses during postnatal development. PLoS One. 7(5):e37753.

Ehrlich I, Lohrke S, Friauf E. (1999). Shift from depolarizing to hyperpolarizing glycine action in rat auditory neurones is due to age-dependent Cl- regulation. J Physiol. 1:121-137.

Flint AC, Liu X, Kriegstein AR. (1998). Nonsynaptic glycine receptor activation during early neocortical development. Neuron 20: 43–53.

Friauf E, Wenz M, Oberhofer M, Nothwang HG, Balakrishnan V, Knipper M, Löhrke S. (2008). Hypothyroidism impairs chloride homeostasis and onset οφ inhibitory neurotransmission in developing auditory brainstem and hippocampal neurons. Eur J Neurosci 28:2371-2380. Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H. (2006). GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 43: 589–593.

Hadjab-Lallemend S, Wallis K, van Hogerlinden M, Dudazy S, Nordström K, Vennström B, Fisahn A. (2010). A mutant thyroid hormone receptor alpha1 alters hippocampal circuitry and reduces seizure susceptibility in mice. Neuropharmacol 58(7):1130-9.

Hennou S, Khalilov I, Diabira D, Ben-Ari Y, Gozlan H. (2002). Early sequential formation of functional GABAA and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus. Eur J Neurosci 16: 197–208.

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Ji F, Kanbara N, Obata K. (1999). GABA and histogenesis in fetal and neonatal mouse brain lacking both the isoforms of glutamic acid decarboxylase. Neurosci Res 33: 187–194.

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Leinekugel X, Medina I, Khalilov I, Ben-Ari Y, Khazipov R. (1997). Ca2+ oscillations mediated by the synergistic excitatory actions of GABAA and NMDA receptors in the neonatal hippocampus. Neuron 18: 243–255.

LoTurco JJ, Blanton MG. Kriegstein AR (1991). Initial expression and endogenous activation of NMDA channels in early neocortical development. J Neurosci 11: 792–799.

LoTurco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR. (1995). GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15: 1287–1298.

Owens DF, Liu X, Kriegstein AR. (1999). Changing properties of GABAA receptor-mediated signalling during early neocortical development. J Neurophysiol 82: 570–583.

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. Tyzio R, Represa A, Jorquera I, Ben-Ari Y, Gozlan H, Aniksztejn L. (1999). The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite. J Neurosci 19: 10372–10382.

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Voigt T,Opitz T, deLima AD.(2005). Activation of early silent synapses by spontaneous synchronous network activity limits the range of neocortical connections. J. Neurosci. 25: 4605–4615.

Wang DD, Kriegstein AR. (2008). GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J Neurosci 28: 5547–5558.

Wang DD, Kriegstein AR. (2009). Defining the role of GABA in cortical development. J Physiol. 587:1873-1879. Westerholz S, de Lima AD, Voigt T. (2010). Regulation of early spontaneous network activity and GABAergic neurons development by thyroid hormone. Neuroscience 168: 573–589.

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.

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.

Yeo M, Berglund K, Hanna M, Guo JU, Kittur J, Torres MD, Abramowitz J, Busciglio J, Gao Y, Birnbaumer L, Liedtke WB. (2013). Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc Natl Acad Sci U S A. 110(11):4315-20.