Editors' ChoiceNeuroscience

Two Endogenous Modulators in One

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Science Signaling  25 Jun 2013:
Vol. 6, Issue 281, pp. ec144
DOI: 10.1126/scisignal.2004442

GABAergic signaling mediated by ionotropic γ-aminobutyric acid (GABA) type A receptors (GABAARs) is an important pharmacological target because reduction in inhibitory GABAergic signaling is associated with anxiety and seizures. GABAARs are composed of five subunits, and at the interface between two of these is an allosteric modulatory site, where benzodiazepines bind to enhance GABAAR activity in the presence of GABA (see Harward and McNamara). The presence of this allosteric site sparked the hypothesis that there are endogenously produced regulators that bind this site (endozepines) and peptides encoded by Diazepam binding inhibitor (Dbi) function as negative allosteric modulators. Christian et al. focused on the thalamic reticular nucleus (nRT) because abnormal oscillatory activity in this region is associated with absence seizures. Compared to wild-type mice, mice with a GABAAR with a mutation in the allosteric modulatory site or nm1054 mice with a genomic deletion encompassing Dbi exhibited reduced inhibitory postsynaptic currents (IPSCs) in the nRT and IPSCs were not affected by application of flumazenil, a benzodiazepine antagonist. Viral transduction of DBI into the nRT increased IPSCs and conferred responsiveness to flumazenil in the nm1054 mice. Because GABAARs can be composed of different combinations of subunits, the authors placed “sniffer patches,” which are outside-out membrane patches from the ventrobasal nucleus (VB) in the nRT or the VB, and measured their response to uncaging of GABA. When placed in the nRT from wild-type mice, the sniffer patches exhibited enhanced IPSCs compared with those placed in the VB; when placed in the nRT region of slices from nm1054 mice, there was no potentiation of IPSCs. Thus, Dbi produces positive allosteric modulators in the nRT, not in the VB. Mutant mice that could not respond to the endogenous positive allosteric modulators or could not produce these modulators exhibited higher incidence of spontaneous and pharmacologically induced brain activity associated with seizures, confirming the importance of this endogenous positive allosteric modulation. Thus, Dbi appears to encode both positive and negative allosteric modulators that bind the benzodiazepine site of GABAARs.

C. A. Christian, A. G. Herbert, R. L. Holt, K. Peng, K. D. Sherwood, S. Pangratz-Fuehrer, U. Rudolph, J. R. Huguenard, Endogenous positive allosteric modulation of GABAA receptors by Diazepam binding inhibitor. Neuron 78, 1–12 (2013). [PubMed]

S. C. Harward, J. O. McNamara, In search of the ever-elusive positive endozepine. Neuron 78, 951–952 (2013). [Online Journal] [PubMed]