Compensatory alteration of inhibitory synaptic circuits in cerebellum and thalamus of gamma-aminobutyric acid type A receptor alpha1 subunit knockout mice
- PMID: 16485284
- DOI: 10.1002/cne.20866
Compensatory alteration of inhibitory synaptic circuits in cerebellum and thalamus of gamma-aminobutyric acid type A receptor alpha1 subunit knockout mice
Abstract
Targeted deletion of the alpha1 subunit gene results in a profound loss of gamma-aminobutyric acid type A (GABA(A)) receptors in adult mouse brain but has only moderate behavioral consequences. Mutant mice exhibit several adaptations in GABA(A) receptor subunit expression, as measured by Western blotting. By using immunohistochemistry, we investigated here whether these adaptations serve to replace the missing alpha1 subunit or represent compensatory changes in neurons that normally express these subunits. We focused on cerebellum and thalamus and distinguished postsynaptic GABA(A) receptor clusters by their colocalization with gephyrin. In the molecular layer of the cerebellum, alpha1 subunit clusters colocalized with gephyrin disappeared from Purkinje cell dendrites of mutant mice, whereas alpha3 subunit/gephyrin clusters, presumably located on dendrites of Golgi interneurons, increased sevenfold, suggesting profound network reorganization in the absence of the alpha1 subunit. In thalamus, a prominent increase in alpha3 and alpha4 subunit immunoreactivity was evident, but without change in regional distribution. In the ventrobasal complex, which contains primarily postsynaptic alpha1- and extrasynaptic alpha4-GABA(A) receptors, the loss of alpha1 subunit was accompanied by disruption of gamma2 subunit and gephyrin clustering, in spite of the increased alpha4 subunit expression. However, in the reticular nucleus, which lacks alpha1-GABA(A) receptors in wild-type mice, postsynaptic alpha3/gamma2/gephyrin clusters were unaffected. These results demonstrate that adaptive responses in the brain of alpha1(0/0) mice involve reorganization of GABAergic circuits and not merely replacement of the missing alpha1 subunit by another receptor subtype. In addition, clustering of gephyrin at synaptic sites in cerebellum and thalamus appears to be dependent on expression of a GABA(A) receptor subtype localized postsynaptically.
Similar articles
-
Alteration of GABAergic synapses and gephyrin clusters in the thalamic reticular nucleus of GABAA receptor alpha3 subunit-null mice.Eur J Neurosci. 2006 Sep;24(5):1307-15. doi: 10.1111/j.1460-9568.2006.05006.x. Eur J Neurosci. 2006. PMID: 16987218
-
Reorganization of GABAergic circuits maintains GABAA receptor-mediated transmission onto CA1 interneurons in alpha1-subunit-null mice.Eur J Neurosci. 2007 Jun;25(11):3287-304. doi: 10.1111/j.1460-9568.2007.05558.x. Eur J Neurosci. 2007. PMID: 17552997
-
Glycine and GABA(A) receptor subunits on Renshaw cells: relationship with presynaptic neurotransmitters and postsynaptic gephyrin clusters.J Comp Neurol. 2002 Mar 12;444(3):275-89. doi: 10.1002/cne.10148. J Comp Neurol. 2002. PMID: 11840480
-
GABAA receptors in the thalamus: alpha4 subunit expression and alcohol sensitivity.Alcohol. 2007 May;41(3):177-85. doi: 10.1016/j.alcohol.2007.03.010. Epub 2007 May 23. Alcohol. 2007. PMID: 17521848 Review.
-
The enigma of transmitter-selective receptor accumulation at developing inhibitory synapses.Cell Tissue Res. 2003 Mar;311(3):271-6. doi: 10.1007/s00441-002-0694-9. Epub 2003 Feb 11. Cell Tissue Res. 2003. PMID: 12658435 Review.
Cited by
-
The gephyrin scaffold modulates cortical layer 2/3 pyramidal neuron responsiveness to single whisker stimulation.Sci Rep. 2024 Feb 20;14(1):4169. doi: 10.1038/s41598-024-54720-7. Sci Rep. 2024. PMID: 38379020 Free PMC article.
-
Role of α1-GABAA receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression.J Psychopharmacol. 2024 Feb;38(2):188-199. doi: 10.1177/02698811241227672. Epub 2024 Jan 31. J Psychopharmacol. 2024. PMID: 38293836 Free PMC article.
-
Recent Progress on Genetically Modified Animal Models for Membrane Skeletal Proteins: The 4.1 and MPP Families.Genes (Basel). 2023 Oct 15;14(10):1942. doi: 10.3390/genes14101942. Genes (Basel). 2023. PMID: 37895291 Free PMC article. Review.
-
Conformational state-dependent regulation of GABAA receptor diffusion and subsynaptic domains.iScience. 2022 Oct 29;25(11):105467. doi: 10.1016/j.isci.2022.105467. eCollection 2022 Nov 18. iScience. 2022. PMID: 36388998 Free PMC article.
-
Suprachiasmatic to paraventricular nuclei interaction generates normal food searching rhythms in mice.Front Physiol. 2022 Oct 6;13:909795. doi: 10.3389/fphys.2022.909795. eCollection 2022. Front Physiol. 2022. PMID: 36277219 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Miscellaneous