Regulating anxiety with extrasynaptic inhibition.

Nature Neuroscience

PubMedID: 26322928

Botta P, Demmou L, Kasugai Y, Markovic M, Xu C, Fadok JP, Lu T, Poe MM, Xu L, Cook JM, Rudolph U, Sah P, Ferraguti F, Lüthi A. Regulating anxiety with extrasynaptic inhibition. Nat Neurosci. 2015;18(10):1493-500.
Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C d (PKCd) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCd(+) neurons via extrasynaptic inhibition mediated by a5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes.