, 1998). Therefore, it is possible that extracellular concentrations of endogenous DBI peptides in discrete areas such as nRT are at a lower level that is more likely to exert PAM rather than NAM effects. In contrast to the stark nRT versus VB differences in physiological PAM effects of DBI, immunoreactivity to DBI was observed in both nRT selleck kinase inhibitor and VB (Figure 5). In this regard, it is important to note that DBI is also known as ACBP and the Dbi/Acbp gene is thought to ubiquitously serve housekeeping functions ( Knudsen et al., 1993), generating

an intracellular protein critically involved in facilitating intracellular transport of Acyl-CoA. We hypothesize that the nRT versus

VB differences in the electrophysiological findings likely represent nucleus-specific differences in the extracellular release and processing of DBI. In the current studies, we used a viral strategy to examine whether Dbi gene products are necessary and sufficient to produce endozepine actions in nRT. Although it is possible that viral introduction of DBI into a system in this way induces changes in its modulatory effects, it is unlikely that this explains the PAM actions observed here, as a recent report using similar viral vectors to express DBI and ODN GW786034 clinical trial in the SVZ exclusively observed NAM effects ( Alfonso et al., 2012). The mechanism(s) underlying these differences remain to be determined, though one possible explanation is differential intra- or extracellular processing of DBI, the nature of which is specific to certain areas or cell types. It is certainly

conceivable that some DBI fragments exert PAM effects, whereas others are NAMs. In addition, preliminary evidence suggests that exogenous application of DBI does not alter sIPSCs in VB (C.A.C. and unless J.R.H., unpublished data), in contrast to the robust potentiation of uncaging responses when VB sniffer patches are placed in nRT. This further supports a working model in which nRT-specific processing of Dbi gene products underlies the PAM actions. Strikingly, endogenous BZ-mimicking potentiation was observed in nRT, but not in adjacent VB thalamus. This raises the question of why such effects would be specifically localized to nRT, and not VB. Perhaps selection pressure led to evolution of an adaptive specific subcircuit modulation in nRT that reduces the possibility of seizure occurrence. Synaptic inhibition in nRT exerts a prominent desynchronizing effect to reduce the propensity for oscillatory activity (von Krosigk et al., 1993; Huntsman et al., 1999; Schofield et al., 2009), and potentiation of synaptic inhibition by BZs further suppresses oscillations (Huguenard and Prince, 1994a; Sohal and Huguenard, 2003; Sohal et al., 2003).