Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling

作者：Christian Catherine A^*; Huguenard John R

来源：Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(50): 20278-20283.

DOI：10.1073/pnas.1318031110

• thalamus
• glia
• uncaging
• electrophysiology
• epilepsy

Emerging evidence indicates that diazepam-binding inhibitor (DBI) mediates an endogenous benzodiazepine-mimicking (endozepine) effect on synaptic inhibition in the thalamic reticular nucleus (nRT). Here we demonstrate that DBI peptide colocalizes with both astrocytic and neuronal markers in mouse nRT, and investigate the role of astrocytic function in endozepine modulation in this nucleus by testing the effects of the gliotoxin fluorocitrate (FC) on synaptic inhibition and endozepine signaling in the nRT using patch-clamp recordings. FC treatment reduced the effective inhibitory charge of GABA(A) receptor (GABA(A)R)-mediated spontaneous inhibitory postsynaptic currents in WT mice, indicating that astrocytes enhance GABA(A)R responses in the nRT. This effect was abolished by both a point mutation that inhibits classical benzodiazepine binding to GABA(A)Rs containing the alpha 3 subunit (predominant in the nRT) and a chromosomal deletion that removes the Dbi gene. Thus, astrocytes are required for positive allosteric modulation via the alpha 3 subunit benzodiazepine-binding site by DBI peptide family endozepines. Outside-out sniffer patches pulled from neurons in the adjacent ventrobasal nucleus, which does not contain endozepines, show a potentiated response to laser photostimulation of caged GABA when placed in the nRT. FC treatment blocked the nRT-dependent potentiation of this response, as did the benzodiazepine site antagonist flumazenil. When sniffer patches were placed in the ventrobasal nucleus, however, subsequent treatment with FC led to potentiation of the uncaged GABA response, suggesting nucleus-specific roles for thalamic astrocytes in regulating inhibition. Taken together, these results suggest that astrocytes are required for endozepine actions in the nRT, and as such can be positive modulators of synaptic inhibition.

• 出版日期2013-12-10