GABA Itself Promotes the Developmental Switch of Neuronal GABAergic Responses from Excitation to Inhibition

Program in Neuroscience, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Cell (Impact Factor: 32.24). 06/2001; 105(4):521-32. DOI: 10.1016/S0092-8674(01)00341-5
Source: PubMed


GABA is the main inhibitory neurotransmitter in the adult brain. Early in development, however, GABAergic synaptic transmission is excitatory and can exert widespread trophic effects. During the postnatal period, GABAergic responses undergo a switch from being excitatory to inhibitory. Here, we show that the switch is delayed by chronic blockade of GABA(A) receptors, and accelerated by increased GABA(A) receptor activation. In contrast, blockade of glutamatergic transmission or action potentials has no effect. Furthermore, GABAergic activity modulated the mRNA levels of KCC2, a K(+)-Cl(-) cotransporter whose expression correlates with the switch. Finally, we report that GABA can alter the properties of depolarization-induced Ca(2+) influx. Thus, GABA acts as a self-limiting trophic factor during neural development.

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Available from: Alejandro F Schinder, Jan 02, 2015
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    • "Another critical instance with regard to life stage-specifi cities is given by the developmental switch of neuronal GABAergic responses from excitation to inhibition. This switch is dependent on GABA-induced GABA A receptor activation (Ganguly et al. 2001). Therefore, interference with GABA receptors during development and after brain maturation (see AOP III) is likely to cause distinctly diff erent AOs (Westerholz et al. 2010). "
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    ABSTRACT: Abstract The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways.
    Critical Reviews in Toxicology 01/2015; 45(1):83-91. DOI:10.3109/10408444.2014.981331 · 5.10 Impact Factor
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    • "Data suggests that GABA release in the early developing cortex is able to facilitate the transition of cellular responses to GABA from depolarizing to hyperpolarizing (Ganguly et al., 2001). Although this is mainly hypothesized to be an action potential-independent process (Ganguly et al., 2001), depolarization of GABAergic interneurons by thalamocortical afferents may increase the likelihood of this spontaneous release. Although controversial (Leinekugel et al., 1995; Ben-Ari et al., 1997), AMPA receptor-mediated excitation has been shown to play a role in the facilitation of GABA-induced depolarization. "
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    ABSTRACT: The mediodorsal thalamus (MD) represents a fundamental subcortical relay to the prefrontal cortex (PFC), and is thought to be highly implicated in modulation of cognitive performance. Additionally, it undergoes highly conserved developmental stages, which, when dysregulated, can have detrimental consequences. Embryonically, the MD experiences a tremendous surge in neurogenesis and differentiation, and disruption of this process may underlie the pathology in certain neurodevelopmental disorders. However, during the postnatal period, a vast amount of cell loss in the MD occurs. These together may represent an extended critical period for postnatal development, in which disturbances in the normal growth or reduction of the MD afferents to the PFC, can result in PFC-dependent cognitive, affective, or psychotic abnormalities. In this review, we explore the current knowledge supporting this hypothesis of a protracted critical period, and propose how developmental changes in the MD contribute to successful prefrontal cortical development and function. Specifically, we elaborate on the unique properties of MD-PFC connections compared with other thalamocortical afferents in sensory cortices, examine how MD-PFC innervation modulates synaptic transmission in the local prefrontal circuitry, and speculate on what occurs during postnatal development, particularly within the early neonatal stage, as well as juvenile and adolescent periods. Finally, we discuss the questions that remain and propose future experiments in order to provide perspective and novel insights into the cause of neuropsychiatric disorders associated with MD-PFC development.
    Frontiers in Human Neuroscience 01/2015; 8. DOI:10.3389/fnhum.2014.01027 · 2.99 Impact Factor
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    • "The activity of GABA A currents has been estimated by indirect methods. For example, in the immature cortex, depolarizing GABA A transmission can be unveiled by the opening of calcium voltage sensitive channels, which can be quantified by calcium imaging (Canepari et al., 2000; Ganguly et al., 2001). Also voltage sensitive dyes can be used to estimate GABAergic currents in slice preparations (Canepari et al., 2010). "
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    ABSTRACT: Chloride homeostasis has a pivotal role in controlling neuronal excitability in the adult brain and during development. The intracellular concentration of chloride is regulated by the dynamic equilibrium between passive fluxes through membrane conductances and the active transport mediated by importers and exporters. In cortical neurons, chloride fluxes are coupled to network activity by the opening of the ionotropic GABAA receptors that provides a direct link between the activity of interneurons and chloride fluxes. These molecular mechanisms are not evenly distributed and regulated over the neuron surface and this fact can lead to a compartmentalized control of the intracellular concentration of chloride. The inhibitory drive provided by the activity of the GABAA receptors depends on the direction and strength of the associated currents, which are ultimately dictated by the gradient of chloride, the main charge carrier flowing through the GABAA channel. Thus, the intracellular distribution of chloride determines the local strength of ionotropic inhibition and influences the interaction between converging excitation and inhibition. The importance of chloride regulation is also underlined by its involvement in several brain pathologies, including epilepsy and disorders of the autistic spectra. The full comprehension of the physiological meaning of GABAergic activity on neurons requires the measurement of the spatiotemporal dynamics of chloride fluxes across the membrane. Nowadays, there are several available tools for the task, and both synthetic and genetically encoded indicators have been successfully used for chloride imaging. Here, we will review the available sensors analyzing their properties and outlining desirable future developments.
    Frontiers in Cellular Neuroscience 08/2014; 8. DOI:10.3389/fncel.2014.00258 · 4.29 Impact Factor
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