Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever!

Ben-Ari, Yehezkel; Woodin, Melanie A.; Sernagor, Evelyne; Cancedda, Laura; Vinay, Laurent; Rivera, Claudio; Legendre, Pascal; Luhmann, Heiko J.; Bordey, Angélique; Wenner, Peter; Fukuda, Atsuo; Pol, Anthony N. van den; Gaı̈arsa, Jean-Luc; Cherubini, Enrico

doi:10.3389/fncel.2012.00035

Cited by 137 publications

(128 citation statements)

References 164 publications

(288 reference statements)

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“…Despite the extensive electrophysiological data obtained in vitro, which are supported by a wide range of molecular biological studies on the expression patterns and properties of NKCC1 and KCC2 (3,4), the presence of the ontogenetic decrease in [Cl − ] I , and the consequent shift in E GABA , have been and are still being debated (12). A key element in this debate is the absence so far of direct in vivo demonstration of the Cl − shift.…”

Section: Discussion Properties and Advantages Of Lssmclophensor In Nementioning

confidence: 99%

“…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.…”

Section: Intracellular Chloride ([Clmentioning

confidence: 99%

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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.

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119

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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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Section: Discussion Properties and Advantages Of Lssmclophensor In Nementioning

confidence: 99%

Section: Intracellular Chloride ([Clmentioning

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.

Self Cite

119

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“…Certainly, slow active chloride uptake in immature neurons 62 in conjunction with a higher chloride conductance in vivo versus in vitro, for example, due to synaptic 50 or extrasynaptic GABA A R activation, represents a potential candidate 25 . Whether traumatic injury might affect results obtained from in vitro preparations is currently highly debated 28,44 . What could be the developmental function of subthreshold-depolarizing GABAergic transmission in the immature cortex?…”

Section: Discussionmentioning

confidence: 99%

“…2a,b). In an initial set of experiments, mice were administered the analgesic-sedative nitrous oxide to circumvent (I) potential complications of conventional anaesthetics (which are known to interfere with the generation of large-scale Ca 2 þ waves in rodent pups 42,43 ) or (II) recordings in unanaesthetized mice 44 . In agreement with the observed lack of GABA-induced action potential firing (see above), we found that puff application of GABA (100 mM, for definition of the application time see Methods) from an epidurally positioned pipette mostly failed to evoke distinct somatic CaTs in glutamate-responsive cells (Fig.…”

Section: Gaba Depolarizes the Majority Of Cp Neurons At P3-4 In Vivomentioning

confidence: 99%

GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo

et al. 2015

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A large body of evidence from in vitro studies suggests that GABA is depolarizing during early postnatal development. However, the mode of GABA action in the intact developing brain is unknown. Here we examine the in vivo effects of GABA in cells of the upper cortical plate using a combination of electrophysiological and Ca 2 þ -imaging techniques. We report that at postnatal days (P) 3-4, GABA depolarizes the majority of immature neurons in the occipital cortex of anaesthetized mice. At the same time, GABA does not efficiently activate voltage-gated Ca 2 þ channels and fails to induce action potential firing. Blocking GABA A receptors disinhibits spontaneous network activity, whereas allosteric activation of GABA A receptors has the opposite effect. In summary, our data provide evidence that in vivo GABA acts as a depolarizing neurotransmitter imposing an inhibitory control on network activity in the neonatal (P3-4) neocortex.

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“…GAD exists in two isoforms, GAD67 and GAD65, which are encoded by the GAD1 and GAD2 genes [39]. GABA is crucially needed in early developments, neuronal differentiation and in phases of maturation as well [40]. Reduced production or signaling of GABA can cause hyperexcitability state along with cognitive dysfunction [41].…”

Section: Neurotransmitter Signalling and Implications In Asdmentioning

confidence: 99%

Emerging Clues and Altered Metabolic Findings in Autism: Breakthroughs and Prospects from Omics Studies

Mowafy¹

2016

Autism Open Access

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Autism spectrum disorder (ASD) is a pervasive broad-spectrum disorder that involves multifaceted delays in the development of many basic, social, and communication skills. The etiology of ASD is multifactorial and involves interplay among genetic, neurologic, hormonal, metabolic, immune-inflammatory, and environmental factors; which further complicate both the diagnosis and management in affected individuals. This review delineates the underpinnings of clinical challenges posed by ASD, like clinical heterogeneity of patient presentation, unresolved ASD genomic map and deficient drug therapy. Besides, it addresses the emerging pathogenic, etiologic, and diagnostic clues of diverse origins, encompassing genetic-, neurotransmitter-, androgenic-and immunoinflammatory-anomalies in ASD patients, as availed by advances in Omics technologies (like genomics and proteomics). Moreover, as unravelled by metabolomics studies, metabolic flaws that pertain to amino acids, fatty acids, mitochondrial anomalies, and oxidative-stress are highlighted and further correlated with the extent of clinical picture and malbehaviors coherent with ASD patients. Lastly, future directions are underlined to promote and rationalize ASD research so as to help translate its findings into remedy.

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Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever!

Cited by 137 publications

References 164 publications

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

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

GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo

Emerging Clues and Altered Metabolic Findings in Autism: Breakthroughs and Prospects from Omics Studies

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