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Event Title

GABAergic interneurons morphology and function , Altered

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Inhibition of Na+/I- symporter (NIS) decreases TH synthesis leading to learning and memory deficits in children KE Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

GABAergic interneurons are a heterogeneous group of neuronal cells that consist only 10 to 20% of the total neuronal population (Aika et al., 1994; Halasy and Somogyi, 1993) and they have common features to distinguish them from the pyramidal excitatory cells. These include aspiny dendrites and the release of GABA neurotransmitter, which makes them the main inhibitory source in the 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 in that projection neurons send their signals to more distant locations such as the brain or the spinal cord. 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). 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). GABA is the first excitatory transmitter and is crucial during embryogenesis as 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 GABA-mediated depolarizing effects at the post-synaptic neurons in early development are well described (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 relevance during the formation of connections within the network (Wang and Kriegstein, 2010; Ben Ari et al., 2007; Blankenship and Feller, 2010). Furthermore, GABA-mediated depolarisations have recently been shown to promote excitatory synapse formation by facilitating NMDA receptor activation in cortical pyramidal neurons (Wang and Kriegstein, 2008). The effects of depolarizing GABA 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

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). Additionally, GABA-immunohistochemistry can be used for identification and morphometric analysis of the 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, with the use of the primers in interest each time.

Evidence Supporting Taxonomic Applicability

GABAergic 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).


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