Abstract
γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation–chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders.
Highlights
Reviewed by: Yehezkel Ben-Ari, Institut National de la Santé et de la Recherche Médicale, France Laura Cancedda, Istituto Italiano di Tecnologia, Italy
Autism comprises a heterogeneous group of neuro-developmental disorders known as autism spectrum disorders (ASDs) characterized by deficits in verbal and non-verbal communication, social interaction, restricted interests, and stereotyped behavior [1]
Studies from animal models of ASDs indicate that a dysfunction in GABAergic signaling within particular neuronal circuits may account for most of the clinical symptoms found in autistic patients
Summary
Reviewed by: Yehezkel Ben-Ari, Institut National de la Santé et de la Recherche Médicale, France Laura Cancedda, Istituto Italiano di Tecnologia, Italy. ASDs share overlapping symptoms, indicating common deficits in some neuro-developmental pathways. One of these involves the γ-aminobutyric acid (GABA)Amediated neurotransmission, known to play a crucial role in synaptic tuning and neuronal wiring in late pre and early postnatal days [3]. Γ-Aminobutyric acid is the main inhibitory neurotransmitter in the adult mammalian brain It inhibits neuronal firing by activating two different classes of receptors, GABAA and GABAB. In particular conditions and during brain maturation the intracellular chloride concentration [Cl−]i rises in such a way that the opening of anion channels by GABA produces a chloride efflux and a membrane depolarization that through the activation of a persistent noninactivating sodium conductance [5] may reach the threshold for action potential generation [6, 7]. GABAinduced membrane depolarization facilitates calcium entry via voltage-dependent calcium channels and N -methyl-d-aspartate www.frontiersin.org
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