Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives

Deidda, Gabriele; Bozarth, Ignacio Fernandez; Cancedda, Laura

doi:10.3389/fncel.2014.00119

Cited by 163 publications

(167 citation statements)

References 350 publications

(484 reference statements)

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“…67 In addition to alterations in gastric functions, disturbances of tonic GABA A inhibition are also associated with a wide range of psychiatric, neurological and neurodevelopmental conditions including autism spectrum disorder, depression, and cognitive impairments. [68][69][70] Benzodiazepines, barbiturates, ethanol, and neurosteroids, such as estrogen, all act as allosteric modulators of GABA A receptor efficacy and/or affinity and therefore exert control over this inhibitory network. 71,72 Low concentrations of ethanol, for example, enhance GABA A receptor activation, whereas high concentrations of ethanol can activate the receptor independently of GABA.…”

Section: Vagal Sensorimotor Neurocircuitsmentioning

confidence: 99%

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility

McMenamin

Travagli

Browning

2016

Exp Biol Med (Maywood)

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The gastrointestinal tract receives extrinsic innervation from both the sympathetic and parasympathetic nervous systems, which regulate and modulate the function of the intrinsic (enteric) nervous system. The stomach and upper gastrointestinal tract in particular are heavily influenced by the parasympathetic nervous system, supplied by the vagus nerve, and disruption of vagal sensory or motor functions results in disorganized motility patterns, disrupted receptive relaxation and accommodation, and delayed gastric emptying, amongst others. Studies from several laboratories have shown that the activity of vagal efferent motoneurons innervating the upper GI tract is inhibited tonically by GABAergic synaptic inputs from the adjacent nucleus tractus solitarius. Disruption of this influential central GABA input impacts vagal efferent output, hence gastric functions, significantly. The purpose of this review is to describe the development, physiology, and pathophysiology of this functionally dominant inhibitory synapse and its role in regulating vagally determined gastric functions.

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Section: Vagal Sensorimotor Neurocircuitsmentioning

confidence: 99%

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility

McMenamin

Travagli

Browning

2016

Exp Biol Med (Maywood)

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“…Although they have made great progress, these tools still have some disadvantages such as inevitable changes in the ionic/pH balance between the intracellular and extracellular milieu [1,16,17]. In addition, in the case of Cl - /anion channel rhodopsins, the direction of the membrane potential change should be dependent on the Cl - -equilibrium potential, which can be affected by many factors such as development, localization and disease [18–25]. On the other hand, a new microbial rhodopsin named KR2 from the marine flavobacterium Krokinobacter eikastus , was characterized as one of the light-driven Na + pumps that transport Na + from the inside to the outside of the expressed cell under physiological conditions [26].…”

Section: Introductionmentioning

confidence: 99%

A Chimera Na+-Pump Rhodopsin as an Effective Optogenetic Silencer

et al. 2016

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With the progress of optogenetics, the activities of genetically identified neurons can be optically silenced to determine whether the neurons in question are necessary for the network performance of the behavioral expression. This logical induction is expected to be improved by the application of the Na+ pump rhodopsins (NaRs), which hyperpolarize the membrane potential with negligible influence on the ionic/pH balance. Here, we made several chimeric NaRs between two NaRs, KR2 and IaNaR from Krokinobacter eikastus and Indibacter alkaliphilus, respectively. We found that one of these chimeras, named I1K6NaR, exhibited some improvements in the membrane targeting and photocurrent properties over native NaRs. The I1K6NaR-expressing cortical neurons were stably silenced by green light irradiation for a certain long duration. With its rapid kinetics and voltage dependency, the photoactivation of I1K6NaR would specifically counteract the generation of action potentials with less hyperpolarization of the neuronal membrane potential than KR2.

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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.

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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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Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives

Cited by 163 publications

References 350 publications

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility

Inhibitory neurotransmission regulates vagal efferent activity and gastric motility

A Chimera Na+-Pump Rhodopsin as an Effective Optogenetic Silencer

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

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