Key Event Title
|Level of Biological Organization|
Key Event Components
|abnormal neuron morphology||abnormal|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|NIS inhibition and learning and memory impairment||KeyEvent|
|Caenorhabditis elegans||Caenorhabditis elegans||Low||NCBI|
|During brain development||High|
Key Event Description
The GABA-mediated depolarizing effects at the post-synaptic neurons in early development are well documented (Ben-Ari, 2014) and have been greatly correlated with the emergence of spontaneous network activity, which is the first neuronal activity of the brain (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 role during the synaptogenesis and the formation of connections within the neuronal network (Wang and Kriegstein, 2010; Ben Ari et al., 2007; Blankenship and Feller, 2010).
One of the milestones at the critical 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 GABAergic 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).
GABAergic interneurons are a heterogeneous group of neuronal cells that consist only of 10 to 20% of the total neuronal population (Aika et al., 1994; Halasy and Somogyi, 1993). They are characterized by aspiny dendrites and the release of GABA neurotransmitter, which makes them the main inhibitory source in the adult central nervous system (CNS) (Markram et al., 2004). A hallmark of interneurons is their structural and functional diversity. Many different subtypes have been identified in the cortex and hippocampus, but a global classification in specific categories is difficult to be established due to the variable morphological and functional properties (Klausberger and Somogyi, 2008; DeFelipe et al., 2013). The interneurons can be primarily identified by their characteristic morphology, which would divide them into 4 basic groups: basket cells, chandelier cells, bouquet cells and bitufted cells. However, a broader classification of these cells would require at least the following criteria: 1) morphology of soma, axonal and dendritic arbors; 2) molecular markers including but not restricted to calcium binding proteins (parvalbumin, calbindin, calretinin) and neuropeptides (e.g., Vasoactive Intestinal Peptide [VIP], reelin, somatostatin); 3) postsynaptic target cells; and 4) functional characteristics (Ascoli et al., 2008). They are neither motor nor sensory neurons, and also differ from projection neurons which send their signals to more distant locations.
GABAergic interneurons are broadly present throughout the CNS, although telencephalic structures, such as the cerebral cortex and hippocampus, show the most abundant quantities of this neurotransmitter (Jones 1987). Complex interconnections between GABAergic interneurons and pyramidal cells shape the responses of pyramidal cells to incoming inputs, prevent runaway excitation, refine cortical receptive fields, and are involved in the timing and synchronisation of network oscillations (Wehr and Zador, 2003; Markram et al., 2004; LeMaqueresse and Monyer, 2013; Hu et al., 2014).
General role in biology
Inhibitory GABAergic interneurons of the adult nervous system play a vital role in neural circuitry and activity by regulating the firing rate of target neurons (reducing neuronal excitability). In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. Released neurotransmitter typically acts through postsynaptic GABAA ionotropic receptors in order to trigger a neuronal signalling pathway. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization.
During early brain development GABA mediates depolarisation that has recently been shown to promote excitatory synapse formation by facilitating NMDA receptor activation in cortical pyramidal neurons (Wang and Kriegstein, 2008). 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).
GABA plays an important role as the first excitatory transmitter during embryogenesis and it has been shown to affect neurogenesis, differentiation, migration, and integration of developing neurons into neuronal circuits (LoTurco et al., 1995; Heck, et al., 2007).
The effects of GABA being depolarizing are also important in the adult brain, as it has impact on synaptic plasticity and is strongly correlated with seizures (Baram and Hatalski, 1998; Ben-Ari et al., 2012). If GABAergic interneuron function breaks down, excitation takes over, leading to seizures and failure of higher brain functions (Westbrook, 2013)
How It Is Measured or Detected
Parvalbumin (PV) is a marker of GABAergic interneurons that can be identified by immunohistochemistry. GABA or GAD can be used for identification and morphometric analysis of the GABAergic neuronal population (Voigt et al., 2001; De Lima et al., 2007), with the use of anti-GABA antibodies. Protein levels on interneurons can be measured by commercial available antibody sandwich ELISA kits, Western blotting, immunohistochemistry and immunofluorescence and mRNA levels is possible to be measured with RT-PCR.
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 (Voigt et al., 2001). 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
Gamma-aminobutyric acid (GABA)ergic interneurons play a vital role in the wiring and circuitry of the developing nervous system of all organisms, both invertebrates and vertebrates (Hensch, 2005; Owens and Kriegstein, 2002; Wang et al., 2004). However, restricted expression of GABA in a considerable population of neurons is observed in the non-vertebrate animals. A nematode Caenorhabditis elegans has 302 neurons, among them, 26 cells are GABAergic (Sternberg and Horvitz, 1984; McIntire et al., 1993). Another nematode Ascaris has 26 GABAergic neurons (Obata, 2013). Glutamate decarboxylase (GAD), vesicular GABA transporter (VGAT), GABA receptors and GABA-system-specific molecules are analogous to those of vertebrates. Except for one interneuron, GABAergic neurons are connected with muscle cells and exert direct inhibitory, sometimes excitatory, control on locomotion, defecation and foraging. The muscle innervation of both excitatory and inhibitory axons is maintained also in Crustacea (Obata, 2013).
Aika Y, Ren JQ, Kosaka K, Kosaka T. (1994). Quantitative analysis of GABA-like-immunoreactive and parvalbumin-containing neurons in the CA1 region of the rat hippocampus using a stereological method, the disector. Exp. Brain Res. 99: 267–276.
Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G, Benavides-Piccione R, Burkhalter A, Buzsaki G, Cauli B, Defelipe J, Fairen A, et al. (2008). Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9: 557–568.
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.
Baram TZ, Hatalski CG. (1998). Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain. Trends Neurosci 21: 471–476.
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 18:467–486.
Ben-Ari. (2014). The GABA excitatory/inhibitory developmental sequence: a personal journey. Neuroscience 279:187–219.
Blaesse P, Airaksinen MS, Rivera C, Kaila K. (2009). Cation chloride co-transporters and neuronal function. Neuron 61:820–838.
Blankenship AG, Feller MB. (2010). Mechanisms underlying spon¬taneous patterned activity in develop¬ing neural circuits. Nat. Rev. Neurosci. 11:18–29.
DeFelipe J, López-Cruz PL, Benavides-Piccione R, Bielza C, Larrañaga P, Anderson S et al. (2013). New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat Rev Neurosci. 14: 202-216.
deLima AD, Lima BD, Voigt T. (2007). Earliest spontaneous activity differentially regulates neocortical GABAergic interneuron subpopulations. Eur.J.Neurosci. 25: 1–16.
Ganguly K, Schinder AF, Wong ST, Poo M. (2001). GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell 105:521–532.
Halasy K, Somogyi P. (1993). Distribution of GABAergic synapses and their targets in the dentate gyrus of rat: A quantitative immunoelectron microscopic analysis. J. Hirnforsch. 34: 299–308.
Heck N, Kilb W, Reiprich P et al. (2007). GABA-A receptors regulate neocortical neuronalmigration in vitro and in vivo. Cereb Cortex. 17:138–148.
Hensch TK. (2005). Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 6: 877-888.
Hu H, Gan J, Jonas P. (2014). Interneurons. Fast-spiking, parvalbumin⁺ GABAergic interneurons: from cellular design to microcircuit function. Science. 345:1255-1263.
Jones EG. (1987). GABA-peptide neurons in primate cerebral cortex. J Mind Behav 8:519–536.
Klausberger T, Somogyi P. (2008). Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science. 321:53–57.
Le Magueresse C, Monyer H. (2013). GABAergic interneurons shape the functional maturation of the cortex. Neuron. 77:388-405.
LoTurco JJ, Owens DF, Heath MJS, Davis MBE, Kriegstein AR. (1995). GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron. 15: 1287–1298.
Lu J, Karadsheh M, Delpire E. (1999). Developmental regulation of the neuronal-specific isoform of K-Cl cotransporter KCC2 in postnatal rat brains. J Neurobiol 39: 558–568.
Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. (2004). Interneurons of the neocortical inhibitory system. Nature Reviews Neuroscience, 5:793–807.
McIntire SL, Jorgensen E, Kaplan J. and Horvitz, H.R. (1993) The GABAergic nervoussystem of Caenorhabditis elegans. Nature 364, 337–341.
Obata K. (2013).Synaptic inhibition and gamma-aminobutyric acid in the mammalian central nervous system. Proc. Jpn. Acad., Ser. B 89 (2013).
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.
Owens DF, Kriegstein AR. (2002). Is there more to GABA than synaptic inhibition? Nat Rev Neurosci 3:715-727.
Sternberg PW. and Horvitz HR. (1984) The genetic control of cell lineage during nematode
development. Annu. Rev. Genet. 18, 489–524.
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. (2008). GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J Neurosci. 28: 5547–5558.
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.
Wang XJ, Tegner J, Constantinidis C, Goldman-Rakic PS (2004). Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory. Proc Natl Acad Sci U S A. 101: 1368-1373.
Wehr M, Zador AM. (2003). Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex. Nature. 426: 442–446.
Westbrook G. (2013). “Seizures and epilepsy” in Principles of Neural Science, E. Kandel, J. H. Schwartz, T. M. Jessell, S. Siegelbaum, A. J. Hudspeth, Eds. McGraw-Hill, New York: 1116–1139.
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.