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GABAergic interneurons, Decreased leads to Synaptogenesis, Decreased
Key Event Relationship Overview
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|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
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 synapses 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 initial regulator of synaptogenesis. 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; Owens et al., 1999; Tyzio et al., 1999; Hennou et al., 2002; Ben-Ari, 2006). Nascent GABAergic synapses contain both presynaptic and postsynaptic elements, and produce synaptic transmission (Ahmari and Smith, 2002). GABAA receptors form clusters before presynaptic terminals emerge (Scotti and Reuter, 2001), and this clustering occur in the absence of scaffolding proteins and GABA release (Scotti and Reuter, 2001; Christie et al., 2002). Also, during maturation, GABAA receptors become selectively clustered across from terminals that release the neurotransmitter GABA (Craig et al., 1994; Swanwick et al., 2006).
Evidence Collection Strategy
Evidence Supporting this KER
Early in the development of the neocortex, GABAergic interneurons play a role in the formation of 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 suggests that GABAergic signaling is the main regulator of this early neuronal activity, as it is established before the glutamatergic one in the neocortex (Wang and Kriegstein, 2009; Owens et al., 1999; Tyzio et al., 1999; Hennou et al., 2002; Ben-Ari, 2006). Despite the fact that GABA is the main inhibitory neurotransmitter in the adult CNS, 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 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 expressed by GABA neurons is sufficient to shift from the depolarizing and excitatory period of GABA during cortical neuron 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).
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 KER.
• Too early shift of GABA-induced excitation-to-inhibition not only affects 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).
• In the dentate gyrus of the adult hippocampus, newborn granule cells are tonically activated by ambient GABA before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic Cl- ion content (Ge et al., 2006).
• An early hyperpolarizing shift in 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 vitro (Chudotvorova et al., 2005; Akerman and Cline, 2006).
The mechanistic details of this relationship are not entirely known, but the most possible mechanism entails a functional relationship between GABA and NMDA receptor activation (Wang and Kriegstein, 2008; Cserép 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).
Uncertainties and Inconsistencies
In vivo evidence for the role of GABA in synaptogenesis is controversial. Ji et al., 1999 have shown that in GAD65/67-deficient mice, in which the production of GABA was reduced to less than 5%, the development of brain morphology until birth was normal. These mice die at birth and therefore synaptogenesis and circuit development could not be controlled, however no morphological defects were detected in the neocortex, cerebellum and hippocampus of these animals by the time of their death. The authors of this study suggested that GABA may not be crucial for development. However, functional changes were not assessed in this study. One hypothesis is that glutamate, glycine and taurine could compensate for the lack of GABA (LoTurco et al., 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). Moreover, these mice died at birth, before the GABA switch takes place, and neuronal electrical activity or synaptogenesis were not evaluated.
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.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most of the available studies have been performed in rodent models and human cortical neurons, referenced in the "Biological plausibility" section.
The relationship between KCC2 function and GABA signalling has been also demonstrated in the retinotectal circuit of Xenopus (Akerman and Cline, 2006).
Ahmari SE, Smith SJ. (2002). Knowing a nascent synapse when you see it. Neuron. 34:333–336.
Akerman CJ, Cline HT. (2006). Depolarizing GABAergic conductances regulate the balance of excitation to inhibition in the developing retinotectal circuit in vivo. J Neurosci 26: 5117–5130.
Ben-Ari Y. (2006). Basic developmental rules and their implications for epilepsy in the immature brain. Epileptic Disord. Jun; 8(2):91-102.
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.
Christie SB, Miralles CP, De Blas AL. GABAergic innervation organizes synaptic and extrasynaptic GABAA receptor clustering in cultured hippocampal neurons. J Neurosci. 2002;22:684–697.
Craig AM, Blackstone CD, Huganir RL, Banker G. Selective clustering of glutamate and gamma-aminobutyric acid receptors opposite terminals releasing the corresponding neurotransmitters. Proc Natl Acad Sci U S A. 1994;91:12373–12377.
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.
Fisher JW, Li S, Crofton K, Zoeller RT, McLanahan ED, Lumen A, Gilbert ME. (2013). Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model. Toxicol Sci. 132(1):75-86.
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.
Gilbert ME, Hedge JM, Valentin-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW (2013) An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci 132:177-195.
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.
Hübner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ. (2001). Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron. 30:515-524.
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.
Lee H, Chen CX, Liu YJ, Aizenman E, Kandler K. (2005). KCC2 expression in immature rat cortical neurons is sufficient to switch the polarity of GABA responses. Eur J Neurosci. 21: 2593-2599.
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.
López-Espíndola D, Morales-Bastos C, Grijota-Martínez C, Liao XH, Lev D, Sugo E, Verge CF, Refetoff S, Bernal J, Guadaño-Ferraz A. (2014). Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination. J Clin Endocrinol Metab. Dec;99(12):E2799-804.
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.
Scotti AL, Reuter H. Synaptic and extrasynaptic gamma -aminobutyric acid type A receptor clusters in rat hippocampal cultures during development. Proc Natl Acad Sci U S A. 2001;98:3489–3494.
Swanwick CC, Murthy NR, Mtchedlishvili Z, Sieghart W, Kapur J. Development of gamma-aminobutyric acidergic synapses in cultured hippocampal neurons. J Comp Neurol. 2006 Apr 10;495(5):497-510
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.
Voigt T, Opitz T, De Lima AD. (2001). Synchronous oscillatory activity in immature cortical network is driven by GABAergic preplate neurons. J Neurosci 21: 8895–8905.
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.
Wu Y, Beland FA1, Fang JL. (2016). Effect of triclosan, triclocarban, 2,2',4,4'-tetrabromodiphenyl ether, and bisphenol A on the iodide uptake, thyroid peroxidase activity, and expression of genes involved in thyroid hormone synthesis. Toxicol In Vitro. Apr;32:310-9.
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.