Increased serotonin transporter expression reduces fear and recruitment of parvalbumin interneurons of the amygdala

Journal article

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.

Authors: Bocchio, M; Fucsina, G; Oikonomidis, L; McHugh, S; Bannerman, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Publishing Group
• Journal: Neuropsychopharmacology
• Volume: 40
• Pages: 3015–3026
• Publication date: 2015-12-01
• Acceptance date: 2015-05-26
• DOI: 10.1038/npp.2015.157
• ISSN: 1740-634X and 0893-133X
• Pmid: 26052039
• Language: English
• Keywords: interneurons; parvalbumins; receptor, serotonin, 5-HT2A; action potentials; animals; immunohistochemistry; proto-oncogene proteins c-fos; conditioning (psychology); freezing reaction, cataleptic; electroshock; basolateral nuclear complex; fear; neural inhibition; mice, inbred CBA; mice, inbred C57BL; auditory perception; tissue culture techniques; female; patch-clamp techniques; mice, transgenic; serotonin plasma membrane transport proteins; SBTMR