When Are Depolarizing GABAergic Responses Excitatory?

Abstract

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.

Loss of KCC2 in GABAergic Neurons Causes Seizures and an Imbalance of Cortical Interneurons

“…In the developing brain, GABA acts contrastingly to its function in adult CNS by stimulating multiple processes of neuronal development ( Platel et al, 2010 ; Luhmann et al, 2015 ; Wu and Sun, 2015 ). Immature neurons do not strongly express KCC2, but express a Na-K-Cl transporter NKCC1, which increases internal [Cl – ], often resulting in depolarizing responses that increase neuronal excitability and may elicit intracellular calcium transients ( Kaila et al, 2014 ; Schulte et al, 2018 ), though whether GABAergic depolarization is always able to directly excite developing neurons in vivo remains a matter of debate ( Kirmse et al, 2015 ; Valeeva et al, 2016 ; Murata and Colonnese, 2020 ; Kilb, 2021 ; Ben-Ari and Cherubini, 2022 ). This increased excitability caused by altered Cl – homeostasis has been shown to be necessary for many of the developmental processes driven by GABA ( Ge et al, 2006 ; Cancedda et al, 2007 ; Allene et al, 2008 ; Bortone and Polleux, 2009 ; Inada et al, 2011 ; Young et al, 2012 ; Griguoli and Cherubini, 2017 ; Fukuda, 2020 ; Peerboom and Wierenga, 2021 ).…”

“…Studies show that onset of KCC2 expression is a regulator of neuronal development ( Dehorter et al, 2012 ; Llano et al, 2020 ; Peerboom and Wierenga, 2021 ), which is likely mediated by both transporter and transport-independent functions. For instance, the onset of KCC2 expression coincides with the transition to inhibitory GABA responses ( Dehorter et al, 2012 ; Fukuda, 2020 ; Murata and Colonnese, 2020 ; Kilb, 2021 ) and is tightly coupled to precede emergence of GABAergic synaptic activity ( Kobayashi et al, 2008 ). At the same time, this point marks the cessation of developmental programs driven by depolarizing GABA at appropriate postnatal timepoints.…”

Neurophysiology of the Developing Cerebral Cortex: What We Have Learned and What We Need to Know

“…Electrophysiological differences between in vitro and in vivo preparations have been further reported following the deletion of NKCC1, the primary chloride inward transporter (Graf et al, 2021 ). In vivo reports (Kirmse et al, 2015 ; Murata and Colonnese, 2020 ) and modeling studies (Lombardi et al, 2021 ) provide a more complex picture of the developmental shift in GABA action, especially when on-going spatiotemporal interactions between GABAergic and glutamatergic inputs are taken into account (for review Kilb, 2021 ). It is not the aim of this short review to summarize the current data on this topic, but it is well-accepted that the intracellular chloride concentration is regulated by development, various molecular factors, and neuronal activity (Kaila et al, 2014 ; Watanabe and Fukuda, 2015 ; Virtanen et al, 2020 , 2021 ).…”

GABA Receptors Can Depolarize the Neuronal Membrane Potential via Quantum Tunneling of Chloride Ions: A Quantum Mathematical Study

“…The action of depolarization mediated by GABA receptors occurs physiologically during early development or pathologically in certain conditions such as trauma, stroke, and epilepsy [ 1 , 3 , 4 , 5 , 6 ]. The main mechanism behind this depolarization is the increase in the intracellular chloride ions, which makes the Nernst potential less negative [ 7 , 8 ]. The molecular mechanism behind this alteration in the homeostasis of chloride ions concentrations is the abnormal expression of NKCC1 transporter, which loads the chloride ions inside neurons, and KCC2 transporter, which extrudes chloride ions outside the neurons [ 4 , 5 , 6 , 8 ].…”

“…The main mechanism behind this depolarization is the increase in the intracellular chloride ions, which makes the Nernst potential less negative [ 7 , 8 ]. The molecular mechanism behind this alteration in the homeostasis of chloride ions concentrations is the abnormal expression of NKCC1 transporter, which loads the chloride ions inside neurons, and KCC2 transporter, which extrudes chloride ions outside the neurons [ 4 , 5 , 6 , 8 ]. The higher expression of NKCC1 and the lower expression of KCC2 leads to increased intracellular chloride ions concentration, which results in membrane depolarization mediated by chloride ions efflux [ 4 , 5 , 6 , 8 ].…”