Developmental Seizures and Mortality Result from Reducing GABAA Receptor α2-subunit Interaction with Collybistin

Authors

Rochelle M. Hines, University of Nevada, Las Vegas; Tufts University School of MedicineFollow
Hans Michael Maric, University of Würzburg
Dustin J. Hines, University of Nevada, Las Vegas; Tufts University School of MedicineFollow
Amit Modgil, Tufts University School of Medicine
Patrizia Panzanelli, University of Turin
Yasuko Nakamura, Tufts University School of Medicine
Anna J. Nathanson, Tufts University School of Medicine
Alan Cross, Biotech Unit
Tarek Deeb, Tufts University School of Medicine; AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience
Nicholas J. Brandon, AstraZeneca Neuroscience iMED, Biotech Unit; AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience
Paul Davies, Tufts University School of Medicine
Jean-Marc Fritschy, University of Zurich
Hermann Schindelin, University of Würzburg
Stephen J. Moss, Tufts University School of Medicine; AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience; University College

Document Type

Article

Publication Date

8-7-2018

Publication Title

Nature Communications

Volume

9

First page number:

1

Last page number:

15

Abstract

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development.

Disciplines

Biological Psychology

File Format

pdf

File Size

3.354 Kb

Language

English

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Repository Citation

Hines, R. M., Maric, H. M., Hines, D. J., Modgil, A., Panzanelli, P., Nakamura, Y., Nathanson, A. J., Cross, A., Deeb, T., Brandon, N. J., Davies, P., Fritschy, J., Schindelin, H., Moss, S. J. (2018). Developmental Seizures and Mortality Result from Reducing GABAA Receptor α2-subunit Interaction with Collybistin. Nature Communications, 9 1-15.
http://dx.doi.org/10.1038/s41467-018-05481-1