Respiratory and behavioral dysfunction following loss of the GABAA receptor α4 subunit
Article first published online: 5 FEB 2013
© 2013 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Brain and Behavior
Volume 3, Issue 2, pages 104–113, March 2013
How to Cite
Loria, C. J., Stevens, A. M., Crummy, E., Casadesus, G., Jacono, F. J., Dick, T. E. and Siegel, R. E. (2013), Respiratory and behavioral dysfunction following loss of the GABAA receptor α4 subunit. Brain and Behavior, 3: 104–113. doi: 10.1002/brb3.122
- Issue published online: 14 MAR 2013
- Article first published online: 5 FEB 2013
- Manuscript Accepted: 2 JAN 2013
- Manuscript Revised: 21 DEC 2012
- Manuscript Received: 12 OCT 2012
- National Institutes of Health. Grant Number: NS59648
- CWRU/Cleveland Clinic
- CTSA. Grant Numbers: UL1 RR024989, HL087377
- VA Research Service. Grant Number: I01BX000873
- Control of breathing;
- GABAA receptor subunits;
- ventilatory response
γ-Aminobutyric acid type A (GABAA) receptor plasticity participates in mediating adaptation to environmental change. Previous studies in rats demonstrated that extrasynaptic GABAA receptor subunits and receptors in the pons, a brainstem region involved in respiratory control, are upregulated by exposure to sustained hypobaric hypoxia. In these animals, expression of the mRNA encoding the extrasynaptic α4 subunit rose after 3 days in sustained hypoxia, while those encoding the α6 and δ subunits increased dramatically by 2 weeks. However, the participation of extrasynaptic subunits in maintaining respiration in normoxic conditions remains unknown. To examine the importance of α4 in a normal environment, respiratory function, motor and anxiety-like behaviors, and expression of other GABAA receptor subunit mRNAs were compared in wild-type (WT) and α4 subunit-deficient mice. Loss of the α4 subunit did not impact frequency, but did lead to reduced ventilatory pattern variability. In addition, mice lacking the subunit exhibited increased anxiety-like behavior. Finally, α4 subunit loss resulted in reduced expression of other extrasynaptic (α6 and δ) subunit mRNAs in the pons without altering those encoding the most prominent synaptic subunits. These findings on subunit-deficient mice maintained in normoxia, in conjunction with earlier findings on animals maintained in chronic hypoxia, suggest that the expression and regulation of extrasynaptic GABAA receptor subunits in the pons is interdependent and that their levels influence respiratory control as well as adaptation to stress.