A positive for GABA

Neuron 78, 1063–1074 (2013)

Credit: JOSEPH LYNCH

GABA is an inhibitory neurotransmitter that acts in various pathways, including the modulation of the susceptibility and duration of absence seizures, common brief lapses of consciousness. Benzodiazepines are psychoactive synthetic compounds that target GABA_A receptors and can act as either positive (PAM) or negative (NAM) allosteric modulators. On the basis of the presence of an endogenous set of inhibitors comprising DBI and related proteins, which bind the allosteric benzodiazepine site on GABA_A receptors to act as NAMs, Christian et al. suspected that an endogenous PAM might also exist. In their search for a PAM, the authors unexpectedly found a clue that linked back to DBI: mice with either a point mutation that abolished benzodiazepine binding in GABA_A receptors or a chromosomal deletion that included the Dbi gene showed a decrease in the duration of GABA_A receptor–mediated spontaneous inhibitory postsynaptic currents (IPSCs). Experiments with a benzodiazepine site antagonist provided in vitro validation that the benzodiazepine site is targeted by the PAM in modulating the IPSC duration, and electroencephalogram recordings of the mutant mice found that Dbi gene products suppressed seizure activity. Further experiments using caged GABA and GABA transporter antagonists served to define the specific brain regions, relevant to the antiseizure activity, where DBI products behave as PAMs. These results suggest that endogenous benzodiazepine-mimicking PAM effects exist and that they are mediated by DBI proteins.