Presynaptic Regulation of Tonic Inhibition by Neuromodulatory Transmitters in the Basal Amygdala

Abstract

Tonic inhibition mediated by ambient levels of GABA that activate extrasynaptic GABAA receptors emerges as an essential factor that tunes neuronal network excitability in vitro and shapes behavioral responses in vivo. To address the role of neuromodulatory transmitter systems on this type of inhibition, we employed patch clamp recordings in mouse amygdala slice preparations. Our results show that the current amplitude of tonic inhibition (Itonic) in projection neurons of the basal amygdala (BA) is increased by preincubation with the neurosteroid THDOC, while the benzodiazepine diazepam is ineffective. This suggests involvement of THDOC sensitive δ subunit containing GABAA receptors in mediating tonic inhibition. Moreover, we provide evidence that the neuromodulatory transmitters NE, 5HT, and ACh strongly enhance spontaneous IPSCs as well as Itonic in the BA. As the increase in frequency, amplitude, and charge of sIPSCs by these neuromodulatory transmitters strongly correlated with the amplitude of Itonic, we conclude that spill-over of synaptic GABA leads to activation of Itonic and thereby to dampening of amygdala excitability. Since local injection of THDOC, as a positive modulator of tonic inhibition, into the BA interfered with the expression of contextual fear memory, our results point to a prominent role of Itonic in fear learning.

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Acknowledgements

We thank Kathrin Friese, Colette Obst, Regina Ziegler, and Evelyn Friedl for excellent technical assistance.

Funding

Funding was provided by the Deutsche Forschungsgemeinschaft (SFB 779, TP B6) and by the EU Joint Programme-Neurodegenerative Disease Research (JPND) project CIRCPROT (jointly funded by BMBF and EU Horizon 2020 grant agreement No 643417).

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Correspondence to S. Meis or V. Lessmann.

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Meis, S., Endres, T., Munsch, T. et al. Presynaptic Regulation of Tonic Inhibition by Neuromodulatory Transmitters in the Basal Amygdala. Mol Neurobiol 55, 8509–8521 (2018). https://doi.org/10.1007/s12035-018-0984-1

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Keywords

  • Amygdala
  • Tonic inhibition
  • GABA
  • Norepinephrine
  • Nicotine
  • 5HT