Chloride transporter activities shape early brain circuit development

Kirmse, Knut; Holthoff, Knut

doi:10.1016/b978-0-12-815318-5.00004-2

Cited by 1 publication

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“…About 30–40 years ago it was first published that GABA A receptors can mediate depolarizing and even excitatory membrane responses in the immature brain (Mueller et al, 1983 ; Ben-Ari et al, 1989 ; Luhmann and Prince, 1991 ), in contrast to the general textbook knowledge that GABA mediates inhibitory and mostly hyperpolarizing neurotransmission in the CNS. In the following decades, it has been shown that depolarizing GABAergic membrane responses play an essential role for cortical development (Ben-Ari, 2002 ; Owens and Kriegstein, 2002 ; Kirmse and Holthoff, 2020 ) and that such depolarizing GABAergic responses can be re-attained under pathophysiological conditions like trauma, stroke or epilepsy (Jaenisch et al, 2010 ; Dzhala et al, 2012 ; Kaila et al, 2014 ; Liu et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

When Are Depolarizing GABAergic Responses Excitatory?

Kilb

2021

Front. Mol. Neurosci.

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The membrane responses upon activation of GABA(A) receptors critically depend on the intracellular Cl− concentration ([Cl−]i), which is maintained by a set of transmembrane transporters for Cl−. During neuronal development, but also under several pathophysiological conditions, the prevailing expression of the Cl− loader NKCC1 and the low expression of the Cl− extruder KCC2 causes elevated [Cl−]i, which result in depolarizing GABAergic membrane responses. However, depolarizing GABAergic responses are not necessarily excitatory, as GABA(A) receptors also reduces the input resistance of neurons and thereby shunt excitatory inputs. To summarize our knowledge on the effect of depolarizing GABA responses on neuronal excitability, this review discusses theoretical considerations and experimental studies illustrating the relation between GABA conductances, GABA reversal potential and neuronal excitability. In addition, evidences for the complex spatiotemporal interaction between depolarizing GABAergic and glutamatergic inputs are described. Moreover, mechanisms that influence [Cl−]i beyond the expression of Cl− transporters are presented. And finally, several in vitro and in vivo studies that directly investigated whether GABA mediates excitation or inhibition during early developmental stages are summarized. In summary, these theoretical considerations and experimental evidences suggest that GABA can act as inhibitory neurotransmitter even under conditions that maintain substantial depolarizing membrane responses.

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Section: Introductionmentioning

confidence: 99%

When Are Depolarizing GABAergic Responses Excitatory?

Kilb

2021

Front. Mol. Neurosci.

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Chloride transporter activities shape early brain circuit development

Cited by 1 publication

References 195 publications

When Are Depolarizing GABAergic Responses Excitatory?

When Are Depolarizing GABAergic Responses Excitatory?

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