title: Increased Serotonin Transporter Expression Reduces Fear and Recruitment of Parvalbumin Interneurons of the Amygdala.
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.
authors.affiliation: MRC Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Marco
authors.identifier: http://orcid.org/0000-0002-7005-3453
authors.initials: M
authors.lastname: Bocchio
authors.affiliation: MRC Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fucsina
authors.affiliation: MRC Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford, UK.|Department of Pharmacology, University of Oxford, Oxford, UK.|Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Oikonomidis
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McHugh
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.affiliation: MRC Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Capogna
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001307:Auditory Perception / Q000502:physiology; D066272:Basolateral Nuclear Complex / Q000502:physiology*; D003213:Conditioning, Psychological / Q000502:physiology; D004597:Electroshock; D005239:Fear / Q000502:physiology*; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D007150:Immunohistochemistry; D007395:Interneurons / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D010320:Parvalbumins; D016760:Proto-Oncogene Proteins c-fos; D044402:Receptor, Serotonin, 5-HT2A; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse