Increased Serotonin Transporter Expression Reduces Fear and Recruitment of Parvalbumin Interneurons of the Amygdala.

Bocchio M
Fucsina G
Oikonomidis L
McHugh SB
Bannerman DM
Sharp T
Capogna M

Human genetic variations in the serotonin transporter appear to underlie susceptibility to psychiatric disorders. Here, we show mechanisms linking serotonin reuptake to emotional behaviour. We discovered that genetically increased expression of the serotonin transporter in mice leads to reduced fear and altered function of nerve cells of the amygdala, a brain region that controls fear responses.

Scientific Abstract

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.

Increased Serotonin Transporter Expression Reduces Fear and Recruitment of Parvalbumin Interneurons of the Amygdala.
(A) Representative basal amygdala (BA) parvalbumin (PV)-expressing neuron from a wild-type (WT) mouse that was activated by fear memory retrieval (shown as c-Fos signal). (B) BA PV neurons of WT mice are activated significantly more by fear memory retrieval than PV neurons of serotonin transporter overexpressing (5-HTTOE) mice, when auditory tone have been paired during the fear memory acquisition session. (C) BA PV neurons of WT mice display a much stronger depolarization than 5-HTTOE PV neurons when serotonin (5-HT; 50 µM) is bath applied. *significant (p < 0.05).
2015.Neuropsychopharmacology, 40(13):3015-26.
Bazelot M, Bocchio M, Kasugai Y, Fischer D, Dodson PD, Ferraguti F, Capogna M
2015.Neuron, 87(6):1290-1303.
Torrecillos F, Tinkhauser G, Fischer P, Green AL, Aziz TZ, Foltynie T, Limousin P, Zrinzo L, Ashkan K, Brown P, Tan H
2018. J. Neurosci., 38(41):8905-8917.
Huang Y, Sun B, Debarros J, Zhang C, Zhan S, Li D, Zhang C, Wang T, Huang P, Lai Y, Brown P, Cao C, Tan H
2021. eLife, 10:e65444.
Blaesse P, Goedecke L, Bazelot M, Capogna M, Pape HC, Jüngling K
2015.J. Neurosci., 35(19):7317-25.
Dodson PD, Dreyer JK, Jennings K, Syed EC, Wade-Martins R, Cragg SJ, Bolam JP, Magill PJ
2016. Proc. Natl. Acad. Sci. U.S.A., 113(15):E2180-8.