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

Kirmse, Knut; Kummer, Michael; Kovalchuk, Yury; Witte, Otto W.; Garaschuk, Olga; Holthoff, Knut

doi:10.1038/ncomms8750

Cited by 196 publications

(236 citation statements)

References 71 publications

(117 reference statements)

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“…In line with the above conclusions, local block of GABA A Rs was found to increase the frequency and horizontal extent of these network events both in the somatosensory (Minlebaev et al, 2007) and occipital (Kirmse et al, 2015) cortex. One interesting aspect is that the generation of Ca 2+ clusters and spindle bursts was largely independent of NKCC1 (Minlebaev et al, 2007;Kirmse et al, 2015). At present, it is not possible to conclusively assess as to which extent a similar situation also applies to other brain regions.…”

Section: Cellular and Network Effects Of Gabaergic Transmission In Thsupporting

confidence: 70%

“…Two-photon Ca 2+ imaging data further suggested that NKCC1-mediated chloride accumulation is critical for the maintenance of depolarizing GABA responses in vivo (Kirmse et al, 2015). An unexpected outcome of this study was that GABA A R activation alone did not suffice to induce action potential firing.…”

Section: Cellular and Network Effects Of Gabaergic Transmission In Thmentioning

confidence: 69%

“…Cell-attached current-clamp recordings from layer 2/3 neurons in mice at postnatal days 3-4 yielded first direct electrophysiological evidence of GABA-dependent depolarization in the intact mammalian brain (Kirmse et al, 2015). Two-photon Ca 2+ imaging data further suggested that NKCC1-mediated chloride accumulation is critical for the maintenance of depolarizing GABA responses in vivo (Kirmse et al, 2015).…”

Section: Cellular and Network Effects Of Gabaergic Transmission In Thmentioning

confidence: 99%

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Functions of GABAergic transmission in the immature brain

Kirmse¹,

Holthoff

2017

E-Neuroforum

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γ-aminobutyric acid (GABA) mediates synaptic inhibition in the adult brain, but acts as a predominantly depolarizing and partially excitatory neurotransmitter in immature neurons. Recent in vivo studies have confirmed important aspects of this concept and at the same time provided clear evidence for mainly inhibitory GABA actions already in the neonatal cortex. First experimental data suggest that depolarizing responses to GABA might contribute to the activity-dependent maturation of neuronal circuits in vivo. Currently, however, a coherent picture of the role of GABAergic synapses in the immature brain cannot be drawn. Elucidating potential developmental functions of GABAergic depolarization therefore remains an important objective for future research.

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Section: Cellular and Network Effects Of Gabaergic Transmission In Thsupporting

confidence: 70%

Section: Cellular and Network Effects Of Gabaergic Transmission In Thmentioning

confidence: 69%

Section: Cellular and Network Effects Of Gabaergic Transmission In Thmentioning

confidence: 99%

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Functions of GABAergic transmission in the immature brain

Kirmse¹,

Holthoff

2017

E-Neuroforum

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“…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)(8)(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).…”

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.

116

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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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“…However, our data revealed that for certain trajectories the achieved positioning accuracy would not suffice the requirements of somatic calcium imaging (here defined as deviations greater than ±2.5 µm). A common problem of in vivo recordings are motion artefacts, for instance, due to heart beat, respiration and gross body movements, especially when recording from lightly anesthetized or awake animals [20]. Deviations resulting from motion artefacts will add to position deviations as detailed above.…”

Section: Positioning Accuracymentioning

confidence: 99%

Method to quantify accuracy of position feedback signals of a three-dimensional two-photon laser-scanning microscope

Kummer

Kirmse

Witte

et al. 2015

Biomed. Opt. Express

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Two-photon laser-scanning microscopy enables to record neuronal network activity in three-dimensional space while maintaining single-cellular resolution. One of the proposed approaches combines galvanometric x-y scanning with piezo-driven objective movements and employs hardware feedback signals for position monitoring. However, readily applicable methods to quantify the accuracy of those feedback signals are currently lacking. Here we provide techniques based on contactfree laser reflection and laser triangulation for the quantification of positioning accuracy of each spatial axis. We found that the lateral feedback signals are sufficiently accurate (defined as <2.5 µm) for a wide range of scan trajectories and frequencies. We further show that axial positioning accuracy does not only depend on objective acceleration and mass but also its geometry. We conclude that the introduced methods allow a reliable quantification of position feedback signals in a cost-efficient, easy-to-install manner and should be applicable for a wide range of two-photon laser scanning microscopes.

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

Cited by 196 publications

References 71 publications

Functions of GABAergic transmission in the immature brain

Functions of GABAergic transmission in the immature brain

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

Method to quantify accuracy of position feedback signals of a three-dimensional two-photon laser-scanning microscope

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