Tonic GABAergic activity facilitates dendritic calcium signaling and short-term plasticity

Abstract

These authors contributed equally to this work. Summary:Brain activity is highly regulated by GABAergic activity, which acts via GABAARs to suppress somatic spike generation as well as dendritic synaptic integration and calcium signaling. Tonic GABAergic conductances mediated by distinct receptor subtypes can also inhibit neuronal excitability and spike output, though the consequences for dendritic calcium signaling are unclear. Here, we use 2-photon calcium imaging in cortical pyramidal neurons and computational modeling to show that low affinity GABAARs containing an a5 subunit mediate a tonic hyperpolarization of the dendritic membrane potential, resulting in deinactivation of voltage-gated calcium channels and a paradoxical boosting of action potential-evoked calcium influx. We also find that GABAergic enhancement of calcium signaling modulates short-term synaptic plasticity, augmenting depolarization-induced suppression of inhibition. These results demonstrate a novel role for GABA in the control of dendritic activity and suggest a mechanism for differential modulation of electrical and biochemical signaling. comments during the preparation of this manuscript, the Yale Center for Research Computing for support with the Yale Farnam high performance cluster, Henner Knust for compound synthesis, Chiristian Miscenic and Marcello Foggetta for cell transfections and membrane preparations, Judith Lengyel, Gregoire Friz, and Maria Karg for cell line generation and radioligand binding assays, and Marie Claire Pflimlin for support with electrophysiological characterization of Compound A selectivity.

Postweaning positive modulation of α5GABAA receptors improves autism‐like features in prenatal valproate rat model in a sex‐specific manner

“…On the other hand, treatment with MP1 – previously seen to improve behavioral deficit and spontaneous neuronal activity in calcium imaging experiments – increased GABRA5 expression in VPA females. Support of our findings and implications can be found in enhanced dendritic calcium influx and short‐term synaptic plasticity following the activation of α5GABAARs (Chiu et al, 2020). The authors proposed that tonic GABAergic conductance leads to hyperpolarization of the dendritic membrane, which de‐inactivates low‐threshold calcium channels and enhances action potential‐evoked calcium influx.…”

Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure

“…However, in support of our findings, optogenetic stimulation of glutamatergic neurons in the mPFC is known to mimic antidepressant drug-induced behavioral effects [18][19][20][21] . Moreover, a tonic form of GABAergic inhibition at pyramidal cell dendrites mediated by α5-GABAA receptors has been shown to de-inactivate low threshold V-gated Ca 2+ channels and potentiate glutamatergic activity-induced Ca 2+ -influx and dendritic spiking of pyramidal cells 46 . Lastly, α5-GABAA receptors represent a promising target for next-generation antidepressants 47,48 .…”

“…We propose that SST neurons are acutely neuro-protective during stress exposure and very high network load by limiting NMDA receptor-mediated Ca 2+ influx into dendrites via activation of prototypical postsynaptic GABAA receptors 44 and by facilitating recovery of pyramidal cells in between stressful periods through potentiation of tonic inhibition, which increases excitability of pyramidal cells. Indeed, tonic inhibition through α5-GABAA receptors at dendrites leads to de-inactivation of t-type Ca 2+ channels and thereby increases dendritic excitability and pyramidal cell output 46 .…”

Aberrant maturation and connectivity of prefrontal cortex in schizophrenia—contribution of NMDA receptor development and hypofunction

“…, SST-INs) GABAergic inhibition 119 . Tonic GABAergic activity also facilitates dendritic calcium signaling and short-term plasticity 120 . Dendritic NMDARs in PV-INs even underlie supralunar integration of feedback excitation from local pyramidal neurons and thus enable strong and stable neuronal assemblies 121 .…”