| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SUBUNIT
1 Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, CA, USA
2 Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, USA
3 Department of Molecular & Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, USA
4 Department of Anesthesiology/CCM, Univ. of Pittsburgh School of Medicine, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: igor{at}ucla.edu.
The 
subunit of the 
-aminobutyric acid (A) receptor (GABAAR) is expressed postnatally mostly in the cerebellum, thalamus and dentate gyrus. Previous studies in mice with a targeted disruption of the subunit revealed a striking attenuation of behavioral responses to neuroactive steroids, but not to other neuromodulatory drugs. Here we show that subunit loss leads to a concomitant reduction in hippocampal 
4 subunit levels. These changes were accompanied by faster decay of evoked inhibitory postsynaptic potentials (IPSPs) in dentate granule neurons of -/- mutants (decay 
=25ms) compared to +/+ controls (=50ms). Furthermore, the miniature GABAAR-mediated synaptic currents (mIPSCs) also decayed faster in -mutants (=6.3ms) than controls (=7.2ms), and had decreased frequency (controls, 10.5Hz; mutants, 6.6Hz). Prolongation of mIPSCs by the neuroactive steroid anesthetic, alphaxalone (1-10µM), was smaller in -mutants (at 10µM, 65% increase) compared to +/+ littermates (308% increase). In competition binding experiments, alphaxalone (0.03-1µM) modulation of [35S]t-butylbicyclophosphorothionate binding was reduced in -mutant brain homogenates, indicating that the decreased alphaxalone effects on mIPSCs were due to changes in the GABAAR protein.
Faster decay of evoked IPSPs and mIPSCs in -mutants suggests presence of the subunit at both synaptic and extrasynaptic GABAARs. Decreased synaptic and extrasynaptic inhibition likely contributes to the pro-epileptic phenotype of -mutants. Reduced neurosteroid sensitivity might also contribute to seizure susceptibility. While the simplest explanation is that subunit-containing GABAARs represent the actual target of neurosteroids, it is possible that the behavioral and physiological sensitivity to neuroactive steroids is indirectly altered in the -/- mice.
This article has been cited by other articles:
|
|
 |
|
  J. Liang, I. Spigelman, and R. W. Olsen Tolerance to Sedative/Hypnotic Actions of GABAergic Drugs Correlates With Tolerance to Potentiation of Extrasynaptic Tonic Currents of Alcohol-Dependent Rats J Neurophysiol, July 1, 2009; 102(1): 224 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Y. Zecharia, L. E. Nelson, T. C. Gent, M. Schumacher, R. Jurd, U. Rudolph, S. G. Brickley, M. Maze, and N. P. Franks The Involvement of Hypothalamic Sleep Pathways in General Anesthesia: Testing the Hypothesis Using the GABAA Receptor {beta}3N265M Knock-In Mouse J. Neurosci., February 18, 2009; 29(7): 2177 - 2187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Lagrange, E. J. Botzolakis, and R. L. Macdonald Enhanced macroscopic desensitization shapes the response of {alpha}4 subtype-containing GABAA receptors to synaptic and extrasynaptic GABA J. Physiol., February 1, 2007; 578(3): 655 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Chandra, F. Jia, J. Liang, Z. Peng, A. Suryanarayanan, D. F. Werner, I. Spigelman, C. R. Houser, R. W. Olsen, N. L. Harrison, et al. GABAA receptor {alpha}4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol PNAS, October 10, 2006; 103(41): 15230 - 15235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Krystal, J. Staley, G. Mason, I. L. Petrakis, J. Kaufman, R. A. Harris, J. Gelernter, and J. Lappalainen {gamma}-Aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment. Arch Gen Psychiatry, September 1, 2006; 63(9): 957 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liang, N. Zhang, E. Cagetti, C. R. Houser, R. W. Olsen, and I. Spigelman Chronic Intermittent Ethanol-Induced Switch of Ethanol Actions from Extrasynaptic to Synaptic Hippocampal GABAA Receptors J. Neurosci., February 8, 2006; 26(6): 1749 - 1758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schwabe, C. Gavrilovici, D. C. McIntyre, and M. O. Poulter Neurosteroids Exhibit Differential Effects on mIPSCs Recorded From Normal and Seizure Prone Rats J Neurophysiol, September 1, 2005; 94(3): 2171 - 2181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Wiltgen, M. J. Sanders, C. Ferguson, G. E. Homanics, and M. S. Fanselow Trace fear conditioning is enhanced in mice lacking the {delta} subunit of the GABAA receptor Learn. Mem., May 1, 2005; 12(3): 327 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Nagele, L. B. Metz, and C. M. Crowder Nitrous oxide (N2O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans PNAS, June 8, 2004; 101(23): 8791 - 8796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. S. Lein, X. Zhao, and F. H. Gage Defining a Molecular Atlas of the Hippocampus Using DNA Microarrays and High-Throughput In Situ Hybridization J. Neurosci., April 14, 2004; 24(15): 3879 - 3889. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
