title: Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice.
abstract: Epidemiological evidence links exposure to stressful life events with increased risk for mental illness. However, there is significant individual variability in vulnerability to environmental risk factors, and genetic variation is thought to play a major role in determining who will become ill. Several studies have shown, for example, that individuals carrying the S (short) allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) have an increased risk for major depression following exposure to stress in adulthood. Identifying the molecular mechanisms underlying this gene-by-environment risk factor could help our understanding of the individual differences in resilience to stress. Here, we present a mouse model of the 5-HTT-by-stress risk factor. Wild-type and heterozygous 5-HTT knockout male mice were subjected to three weeks of chronic psychosocial stress. The 5-HTT genotype did not affect the physiological consequences of stress as measured by changes in body temperature, body weight gain and plasma corticosterone. However, when compared with wild-type littermates, heterozygous 5-HTT knockout mice experiencing high levels of stressful life events showed significantly depressed locomotor activity and increased social avoidance toward an unfamiliar male in a novel environment. Heterozygous 5-HTT knockout mice exposed to high stress also showed significantly lower levels of serotonin turnover than wild-type littermates, selectively in the frontal cortex, which is a structure that is known to control fear and avoidance responses, and that is implicated in susceptibility to depression. These data may serve as a useful animal model for better understanding the increased vulnerability to stress reported in individuals carrying the 5-HTTLPR S allele, and suggest that social avoidance represents a behavioral endophenotype of the interaction between 5-HTT and stress.
authors.affiliation: Department of Evolutionary and Functional Biology, University of Parma, viale G.P. Usberti 11A, Parma, Italy. alessandro.bartolomucci@unipr.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bartolomucci
authors.forename: Valeria
authors.initials: V
authors.lastname: Carola
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pascucci
authors.forename: Stefano
authors.initials: S
authors.lastname: Puglisi-Allegra
authors.forename: Simona
authors.initials: S
authors.lastname: Cabib
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Stefano
authors.initials: S
authors.lastname: Parmigiani
authors.forename: Paola
authors.initials: P
authors.lastname: Palanza
authors.forename: Cornelius
authors.initials: C
authors.lastname: Gross
mesh_terms: D000374:Aggression; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000503:physiopathology
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin