Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

Abstract

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mature brain but has the paradoxical property of depolarizing neurons during early development. Depolarization provided by GABA A transmission during this early phase regulates neural stem cell proliferation, neural migration, neurite outgrowth, synapse formation, and circuit refinement, making GABA a key factor in neural circuit development. Importantly, depending on the context, depolarizing GABA A transmission can either drive neural activity or inhibit it through shunting inhibition. The varying roles of depolarizing GABA A transmission during development, and its ability to both drive and inhibit neural activity, makes it a difficult developmental cue to study. This is particularly true in the later stages of development when the majority of synapses form and GABA A transmission switches from depolarizing to hyperpolarizing. Here, we addressed the importance of depolarizing but inhibitory (or shunting) GABA A transmission in glutamatergic synapse formation in hippocampal CA1 pyramidal neurons. We first showed that the developmental depolarizing-to-hyperpolarizing switch in GABA A transmission is recapitulated in organotypic hippocampal slice cultures. Based on the expression profile of K + −Cl − co-transporter 2 (KCC2) and changes in the GABA reversal potential, we pinpointed the timing of the switch from depolarizing to hyperpolarizing GABA A transmission in CA1 neurons. We found that blocking depolarizing but shunting GABA A transmission increased excitatory synapse number and strength, indicating that depolarizing GABA A transmission can restrain glutamatergic synapse formation. The increase in glutamatergic synapses was activity-dependent but independent of BDNF signaling. Importantly, the elevated number of synapses was stable for more than a week after GABA A inhibitors were washed out. Together these findings point to the ability of immature GABAergic transmission to restrain glutamatergic synapse formation and suggest an unexpected role for depolarizing GABA A transmission in shaping excitatory connectivity during neural circuit development.

Ketamine and Calcium Signaling—A Crosstalk for Neuronal Physiology and Pathology

“…In the same paper, it was suggested that ketamine-dependent inhibition of Ca 2+ transients in immature neurons may be co-mediated by GABA A receptor. In contrast to the adult brain, in the developing hippocampus, GABA acts as excitatory neurotransmitter and depolarizes developing pyramidal neurons through GABA A receptor [52]. At this stage of development, GABA A receptor inhibition should lead to suppression of spontaneous Ca 2+ transients.…”

Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain

“…Studies have demonstrated that the application of GABAA antagonists to organotypic hippocampal neuronal cultures showed marked loss of spines. Upon administration of bicuculline, a GABAA receptor antagonist decreased spine density, explains that absence of hyperpolarizing GABAA transmission resulted in the spine loss [ 76 ]. Activation of GABA receptors suppressed overall cytosolic calcium concentration promoting spine shrinkage and elimination in CA1 region of rat hippocampus.…”

Sex Differences in the Development of the Rodent Corticolimbic System

“…As the brain matures, upregulation of the KCC2 transporter lowers the intracellular chloride concentration, driving GABA A -mediated hyperpolarization (Rivera et al, 1999;Khirug et al, 2005;Ben-Ari et al, 2007Tyzio et al, 2008). This shift in GABAergic transmission plays an important role in the development of hippocampal circuit formation (Leinekugel et al, 1995;Ben-Ari et al, 1997;Cancedda et al, 2007;Wang and Kriegstein, 2008;Kirmse et al, 2015;Oh et al, 2016;Valeeva et al, 2016;Brady et al, 2018;Salmon et al, 2020), and its disruption is implicated in neurodevelopmental disorders (Deidda et al, 2014).…”