These findings are consistent with the presence of an endogenous PAM within nRT of wild-type mice. Christian et al. (2013) provide additional convincing evidence of a PAM residing within nRT by examining an LY2157299 cost adjacent thalamic nucleus—the ventrobasal (VB) nucleus. In contrast to neurons within nRT, a BR antagonist had no effect on the duration of IPSCs of neurons within VB. Might this be due to differences in the nature of GABAARs in the two nuclei? Or might PAM activity be present within nRT but not VB? To distinguish these possibilities, Christian et al. (2013) performed an elegant series of experiments combining “sniffer patches” with GABA uncaging. Outside-out

membrane patches containing GABAARs were obtained from VB cells and then placed into either VB or nRT within thalamic slices. Moving the patches from VB to nRT resulted in an increased duration of the GABA response within nRT compared to VB. These results exclude the Selleck BMS 354825 possibility that differences in composition of GABAARs are sufficient to account for the different responses to the BR antagonist in VB compared to nRT. Instead the results provide powerful support for the presence of a PAM within nRT. In search of the molecular identity of the PAM, Christian et al. (2013) explore DBI—a protein that is highly expressed in nRT and has previously been shown to bind the BR of GABAARs. Using

a mouse lacking a 400 kb region of chromosome 1 (nm1054) containing the Dbi gene plus several others, Christian et al. (2013) detect a reduction of sIPSC duration in the mutant animal compared to wild-type controls. These findings are similar to those observed in mice with a disrupted BR (α3(H126R)). Importantly, the reduced IPSC duration was rescued by viral expression of Dbi, demonstrating

that loss of this gene in particular is sufficient to account for the reduced IPSC duration. These findings Adenylyl cyclase provide strong evidence that the Dbi gene encodes the endogenous PAM within nRT. The fact that inhibition within nRT plays a critical role in regulating thalamic oscillations led Christian et al. (2013) to query whether the reduced duration of IPSCs within nRT neurons might be associated with enhanced sensitivity to absence seizures in a chemoconvulsant model. Indeed, enhanced sensitivity to chemoconvulsant-induced seizures was detected in mice lacking the Dbi gene (nm1054 mice). Similarly, mice with a disrupted BR in their GABAARs (α3(H126R)) exhibited prolonged epileptiform activity in response to the chemoconvulsant. These findings are consistent with the proposal that an endogenous PAM within nRT, specifically encoded by the Dbi gene, reduces susceptibility to absence seizures by enhancing GABAAR function. In sum, this lovely series of experiments establishes the presence of a PAM of GABAAR function that acts through the BR. Additionally, this work narrows the molecular identity of this PAM to a product of a single gene—Dbi; that said, unanswered questions persist.