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Key Event Title
Delay, Developmental GABA shift
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
Biological state: Aminobutyric acid (GABA) is an amino acid, which prevails in the adult nervous system and its conformation depends mainly on its environment. This conformational flexibility of GABA is important for its biological function that changes in the course of the brain development (Ben-Ari et al., 2007). Most of its effects are mediated by the two classes of GABA receptors (GABAA and GABAB). GABAAR is the major inhibitory receptor in the mammalian brain and is a ligand-gated ion channels permeable to chloride and to a lesser extent to bicarbonate anions (Betz, 1990; Miller and Smart, 2010). Up to date 19 GABAAR subunits have been cloned in the mammalian Central Nervous System (CNS). GABABR is a metabotropic receptor, localized in both the pre- and post-synaptic neurons, which belongs to the G protein-coupled receptors, meaning that it opens or closes the ion channels as well but through the G proteins activation (Bettler et al., 2004). GABA is considered as the main inhibitory neurotransmitter in the brain and as such it plays a crucial role in brain physiology, while dysfunction of GABAergic signalling can lead to many pathological conditions in developing and adult nervous systems (Ben-Ari et al., 2007; Ben-Ari et al., 2012). GABAergic signalling has the unique property of "ionic plasticity", which is dependent on short-term and long-term concentration changes of Cl- and HCO3- in the postsynaptic neurons. The intracellular ion concentrations are largely modified in the course of brain development corresponding to the operation and functional modulation of ion transporters, such as the K-Cl co-transporter 2 (KCC2) and the Na-K-Cl co-transporter 1 (NKCC1) (Blaesse et al., 2009; Blankenship and Feller, 2010). One of the milestones at the crucial stage of brain development is the switch of the GABAergic signalling from depolarizing early in life to a more conventional hyperpolarizing inhibition on maturation (Ben-Ari et al., 2007). This developmental switch is mainly driven by the expression change of the predominant potassium-chloride co-transporters (KCC2 and NKCC1) around this period that results in a shift from high to low intracellular Cl− concentration at the post-synaptic neurons (Lu et al., 1999).
Biological compartments: Studies performed in a wide range of developing neuronal structures have confirmed that this process is present in the neocortex, the cerebellum, the spinal cord, the olfactory bulb, sensory structures and several subcortical and peripheral structures (reviewed in Ben-Ari et al., 2007). The GABA switch might occur in a singular dynamic or not occur at all, depending on the neuronal subpopulation. Recent studies have shown that in some synapses formed by specific GABAergic subpopulations remain depolarizing also in adulthood (Woodruff et al., 2009). The same effect was observed in CA3 hippocampal interneurons, which were not undergo the functional switch and remain stunned throughout development (Banke and McBain , 2006). The role of the continuous depolarizing GABAergic action of specific neuronal types is to be elucidated.
General role in biology: GABAergic signalling is crucial for the normal brain function and the regulation of the neuronal activity (Markram et al., 2004). In the mammalian CNS, neuronal intracellular chloride concentration is a fundamental cellular parameter that regulates the inhibitory strength of GABAA and glycine receptors (GABAAR and GlyR respectively). The homeostasis of intraneuronal Cl- concentration, established by the dynamic functional regulation of Cl- channels, transporters, and exchangers, is the major determinant of GABA and glycine function, and it provides to GABAAR and GlyR a unique functional plasticity (Farrant and Kaila, 2007). Specifically, lowering Cl− concentration enhances inhibition of GABA neurotransmission, whereas raising Cl− facilitates spontaneous neuronal activity. The progressive reduction of the intracellular chloride levels during neuronal development and the subsequent shift of GABA signalling from depolarization to hyperpolarization have been suggested to equilibrate glutamatergic and GABAergic neurotransmission (Ben-Ari, 2002), a notion which is further supported by the fact that GABAergic signals mature and function well before the glutamatergic synapses are formed in the brain. In fact, GABA is the main excitatory transmitter during early development, as its depolarizing effects at the post-synaptic neurons during this period are well described (Ben-Ari, 2014). Furthermore, the excitatory potential of GABA has been greatly correlated with the emergence of spontaneous network activity, which is the first neuronal activity of the brain and is generated during the late embryonic and early postnatal stages (Voigt et al., 2001; Opitz et al., 2002;). This spontaneous network activity is characterized by synchronous bursts of action potentials and concomitant intracellular calcium transients in large group of cells and it has been proposed to have functional relevance during the formation of connections within the network (Wang and Kriegstein, 2010; Ben Ari et al., 2007; Blankenship and Feller, 2010). The emergence of this early network activity depends on depolarizing action of GABA (Ben-Ari, 2001) and later the developmental shift of GABAergic signaling has been postulated to induce their gradual disappearance (Allene et al., 2008). In addition, depolarizing GABA has a strong impact on synaptic plasticity and is strongly correlated with seizures, not only in the immature brain but also with epileptic conditions in adult brain (Baram and Hatalski, 1998; Ben-Ari et al., 2012).
How It Is Measured or Detected
Calcium imaging experiments is the most common way to detect the depolarizing action of neurons, as this is correlated with a transient increase in intracellular calcium. The local application of GABA agonist, muscimol, during the calcium imaging has been used the last decades in order to investigate the developmental effects of GABA in the post-synaptic neurons (Owens et al., 1996; Gangulu et al., 2001; Baltz et al., 2010; Westerholz et al., 2013).
Domain of Applicability
There have been performed many studies that confirm that there is a wide range of animal species in which the developmental GABA switch is a common event during neuronal development. From invertebrates, such as worms, to turtles, chicken and a frog, suggesting that it is evolutionary conserved (Ben-Ari et al., 2007). However, the most well- studied structure remains the hippocampus of rats.
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Baltz T, deLima AD, Voigt T. (2010). Contribution of GABAergic interneurons to the development of spontaneous activity patterns in cultured neocortical networks. Front. Cell Neurosci. 4:15.
Banke TG, McBain CJ. (2006). GABAergic input onto CA3 hippocampal interneurons remains shunting throughout development. J Neurosci 26:11720–11725.
Baram TZ, Hatalski CG. (1998). Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain. Trends Neurosci 21: 471–476.
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Opitz T, De Lima AD, Voigt T. (2002). Spontaneous development of synchronous oscillatory activity during maturation of cortical networks in vitro. J Neurophysiol 88:2196–2206.
Owens DF, Boyce LH, Davis MBE, Kriegstein AR. (1996). Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging. J. Neurosci. 16:6414–6423.
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.
Wang DD, Kriegstein AR. 2010. Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits. Cereb Cortex 21:574–587.
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.
Woodruff A, Xu Q, Anderson SA, Yuste R. (2009). Depolarizing effect of neocortical chandelier neurons. Front Neural Circuits. 3:15.