Genetic association studies suggest that variations in the 5-hydroxytryptamine (5-HT; serotonin) transporter (5-HTT) gene are associated with susceptibility to psychiatric disorders such as anxiety or posttraumatic stress disorder. Individuals carrying high 5-HTT-expressing gene variants display low amygdala reactivity to fearful stimuli. Mice overexpressing the 5-HTT (5-HTTOE), an animal model of this human variation, show impaired fear, together with reduced fear-evoked theta oscillations in the basolateral amygdala (BLA). However, it is unclear how variation in 5-HTT gene expression impacts on the microcircuitry of the BLA to change behavior. We addressed this issue by investigating the activity of parvalbumin (PV)-expressing interneurons (PVINs), the biggest IN population in the basal amygdala (BA). We found that increased 5-HTT expression impairs the recruitment of PVINs (measured by their c-Fos immunoreactivity) during fear. Ex vivo patch-clamp recordings demonstrated that the depolarizing effect of 5-HT on PVINs was mediated by 5-HT2A receptor. In 5-HTTOE mice, 5-HT-evoked depolarization of PVINs and synaptic inhibition of principal cells, which provide the major output of the BA, were impaired. This deficit was because of reduced 5-HT2A function and not because of increased 5-HT uptake. Collectively, these findings provide novel cellular mechanisms that are likely to contribute to differences in emotional behaviors linked with genetic variations of the 5-HTT.
