GABAergic Signaling as Therapeutic Target for Autism Spectrum Disorders

Cellot, Giada; Cherubini, Enrico

doi:10.3389/fped.2014.00070

Cited by 242 publications

(229 citation statements)

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“…Several evidences, from animal models to human in vivo and in vitro studies, seem to support this hypothesis (Coghlan et al 2012;Cellot and Cherubini 2014). From a preclinical perspective, animal models of ASD frequently display GABAergic impairment.…”

Section: Introductionmentioning

confidence: 96%

Pharmacological Modulation of GABA Function in Autism Spectrum Disorders: A Systematic Review of Human Studies

Brondino

Fusar-Poli

Panisi

et al. 2015

J Autism Dev Disord

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Autism spectrum disorders are an emerging health problem worldwide, but little is known about their pathogenesis. It has been hypothesized that autism may result from an imbalance between excitatory glutamatergic and inhibitory GABAergic pathways. Commonly used medications such as valproate, acamprosate, and arbaclofen may act on the GABAergic system and be a potential treatment for people with ASD. The present systematic review aimed at evaluating the state-of-the-art of clinical trials of GABA modulators in autism. To date there is insufficient evidence to suggest the use of these drugs in autistic subjects, even if data are promising. Of note, short-term use of all the reviewed medications appears to be safe. Future well designed trials are needed to elucidate these preliminary findings.

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Section: Introductionmentioning

confidence: 96%

Pharmacological Modulation of GABA Function in Autism Spectrum Disorders: A Systematic Review of Human Studies

Brondino

Fusar-Poli

Panisi

et al. 2015

J Autism Dev Disord

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“…However, thus far, there are no direct data on neuronal [Cl − ] i measured in vivo at the single-cell level in the living brain, and for instance, the very existence of the developmental shift in [Cl − ] i described above has been intensely debated (12) because of the lack of such measurements. Moreover, it has been postulated that, in some diseases, such as autism and Down syndrome, the ion-regulatory mechanisms underlying GABA A signaling do not properly mature (12)(13)(14)(15)(16), and E GABA can revert from hyperpolarizing to depolarizing in mature neurons as has been reported for epilepsy and stroke (3,(17)(18)(19). Thus, a technique for monitoring [Cl − ] i in vivo would substantially add to our understanding of Cl − -regulatory mechanisms and their roles in brain development, plasticity, and disease.…”

mentioning

confidence: 99%

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

Sato

Artoni

Landi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

132

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Intracellular chloride ([Cl−] i ) and pH (pH i ) are fundamental regulators of neuronal excitability. They exert wide-ranging effects on synaptic signaling and plasticity and on development and disorders of the brain. The ideal technique to elucidate the underlying ionic mechanisms is quantitative and combined two-photon imaging of [Cl − ] i and pH i , but this has never been performed at the cellular level in vivo. Here, by using a genetically encoded fluorescent sensor that includes a spectroscopic reference (an element insensitive to Cl − and pH), we show that ratiometric imaging is strongly affected by the optical properties of the brain. We have designed a method that fully corrects for this source of error. Parallel measurements of [Cl − ] i and pH i at the single-cell level in the mouse cortex showed the in vivo presence of the widely discussed developmental fall in [Cl − ] i and the role of the K-Cl cotransporter KCC2 in this process. Then, we introduce a dynamic twophoton excitation protocol to simultaneously determine the changes of pH i and [Cl − ] i in response to hypercapnia and seizure activity.I ntracellular ion concentrations are controlled by plasmalemmal transporters and channels, which generate and dissipate ionic electrochemical gradients, respectively (1). In recent years, regulation of the intracellular Cl − concentration ([Cl − ] i ) in neurons has attracted lots of attention, because it is the main ion that carries current across GABA A (and also, glycine) receptors. Changes in [Cl − ] i exert an immediate effect on the reversal potential of GABAergic currents (E GABA ) and, thereby, on the properties of GABA A receptor-mediated transmission (2-4). The "ionic plasticity" of GABAergic signaling involves not only the passive flux of Cl − ions through membrane channels but also, a number of ion transporters that regulate [Cl − ] i . Furthermore, this mechanism is under the control of intracellular signaling cascades that regulate the expression patterns as well as functional properties of ion transporters and channels (5, 6). With regard to long-term ionic modulation of GABAergic transmission, a case in point is the decrease in [Cl − ] i that is generally thought to take place during maturation of most central neurons. According to this widely accepted scenario, the Na-K-2Cl cotransporter NKCC1 accumulates Cl − in immature neurons, thereby promoting depolarizing GABA responses (3, 7-9), which is followed by developmental upregulation of the neuron-specific K-Cl cotransporter KCC2 that is required for the generation of classical hyperpolarizing inhibitory postsynaptic potentials (IPSPs) (10).A wealth of electrophysiological evidence dating back to the work in vivo by Eccles and coworkers (11) has provided evidence for active regulation of [Cl − ] i in mammalian central neurons and its crucial effect on the driving force of Cl − in inhibitory synapses (1). However, thus far, there are no direct data on neuronal [Cl − ] i measured in vivo at the single-cell level in the living brain, and for in...

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“…The paper then discussed the potentials of epigenetic marks as the therapeutic targets in the treatment of neurological disorders [134,135]. Due to its conserved nature and wide range of functions during neurogenesis, it is not surprising that the GABA neurotransmission is highly regulated, genetically and epigenetically, during the development as well as the postnatal stage.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

Shrestha

Offer²

2016

Med Epigenet

6,446

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The GABAergic neurotransmission is a highly conserved system that has been attributed to various regulatory events. There has been a notable number of studies on the importance of GABAergic neurotransmission, both excitatory and inhibitory, in neurogenesis and central nervous system development including its control of neuronal cell proliferation and migration, synaptogenesis, dendrite formation and branching, and new neuronal cell integration in the adult brain. There has been remarkable progress in understanding the epigenetic regulations of GABAergic genes and their aberrant expressions in various neurological disorders such as autism spectrum disorder, Rett's syndrome, schizophrenia and PWS. The roles of histone modifications, chromatin looping and gene methylation have been implicated in altered regulations of key genes in the GABAergic pathway. Taken together, they affect the functioning of GABAergic neurotransmission and disrupt various events in brain development. Here, we focus on the role of GABAergic neurotransmission in brain development and on how various genetic and epigenetic events regulate the GABAergic genes in pre- and postnatal brain. We also discuss how these regulatory mechanisms contribute to the pathogenesis of neurological disorders and, therefore, can be used in the development of potential epigenetic therapy for these diseases.

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GABAergic Signaling as Therapeutic Target for Autism Spectrum Disorders

Cited by 242 publications

References 123 publications

Pharmacological Modulation of GABA Function in Autism Spectrum Disorders: A Systematic Review of Human Studies

Pharmacological Modulation of GABA Function in Autism Spectrum Disorders: A Systematic Review of Human Studies

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

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