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

Neuropsychopharmacology. 2015 Dec;40(13):3015-26. doi: 10.1038/npp.2015.157. Epub 2015 Jun 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Auditory Perception / physiology
  • Basolateral Nuclear Complex / physiology*
  • Conditioning, Psychological / physiology
  • Electroshock
  • Fear / physiology*
  • Female
  • Freezing Reaction, Cataleptic / physiology
  • Immunohistochemistry
  • Interneurons / physiology*
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Neural Inhibition / physiology
  • Parvalbumins / metabolism*
  • Patch-Clamp Techniques
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Tissue Culture Techniques

Substances

  • Parvalbumins
  • Proto-Oncogene Proteins c-fos
  • Receptor, Serotonin, 5-HT2A
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse