Impaired Stress-Coping and Fear Extinction and Abnormal Corticolimbic Morphology in Serotonin Transporter Knock-Out Mice

Abstract

A lesser-expressing form of the human 5-HT transporter (5-HTT) gene has been associated with increased fear and anxiety and vulnerability to the effects of stress. These phenotypic abnormalities are linked to functional and anatomical disturbances in a neural pathway connecting the prefrontal cortex (PFC) and amygdala. Likewise, rodent and nonhuman primate studies indicate a major role for PFC and amygdala in the mediation of fear-and stress-related behaviors. We used a 5-HTT knock-out (KO) mouse to examine the effects of genetically driven loss of 5-HTT function for the following: (1) depression-related behavior in response to repeated stress, and pavlovian fear conditioning, extinction, and extinction recall; and (2) dendritic morphology and spine density of Golgi-stained pyramidal neurons in the infralimbic cortex (IL) and the basolateral amygdala (BLA). 5-HTT KO mice exhibited increased depressive-like immobility after repeated exposure to forced swim stress, compared with wild-type (WT) controls. Whereas fear conditioning and fear extinction was normal, 5-HTT KO mice exhibited a significant deficit in extinction recall. The apical dendritic branches of IL pyramidal neurons in 5-HTT KO mice were significantly increased in length relative to WT mice. Pyramidal neurons in BLA had normal dendritic morphology but significantly greater spine density in 5-HT KO mice compared with WT mice. Together, the present findings demonstrate a specific phenotypic profile of fear-and stress-related deficits in 5-HTT KO mice, accompanied by morphological abnormalities in two key neural loci. These data provide insight into the behavioral sequelae of loss of 5-HTT gene function and identify potential neural substrates underlying these phenotypes.

Presence and acquired origin of reduced recall for fear extinction in PTSD: Results of a twin study

“…However, none of the three comorbid PTSD veterans' unexposed twins shared the comorbidity, suggesting that comorbid depression was a different facet of the same acquired posttraumatic psychopathology. Although research with an animal model suggests that extinction retention may be impaired in depression (Wellman et al, 2007), we are unaware of any human clinical research. Investigation of extinction retention in depression without PTSD appears indicated.…”

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

“…This may be related to stress associated with the ATD procedure, such as the repeated oral injections. Chronic stress is known to impair object memory (Beck and Luine 1999), and there is some evidence to suggest that diminished SERT function is associated with increased stress responsivity in humans (for review, see Canli and Lesch 2007) and mice (Wellman et al 2007). In this way, the injection stress may have resulted in mildly impaired object recognition memory in TRP+ treated SERT −/− rats.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…17,18 5-HTT knockout mice show behaviours consistent with anxious and depressive traits; they appear reluctant to explore brightly lit spaces or elevated open platforms and give up struggling early when put in an uncomfortable situation. [19][20][21] Interestingly, the difference from wild-type animals in depression-like giving-up ('behavioural despair') is manifest only after repeated exposure to stressors, analogous to repeated or chronic stressful life events in humans. 20 The 5-HTT knockout animals also show exaggerated neuroendocrine reactions to acute stress similar to the HPA axis over reactivity in depressed humans.…”

“…[19][20][21] Interestingly, the difference from wild-type animals in depression-like giving-up ('behavioural despair') is manifest only after repeated exposure to stressors, analogous to repeated or chronic stressful life events in humans. 20 The 5-HTT knockout animals also show exaggerated neuroendocrine reactions to acute stress similar to the HPA axis over reactivity in depressed humans. 22,23 The effect of 5-HTT knockout on anxietyand depression-like behaviours may be mediated by the absence of functional serotonin clearance mechanism during a vulnerable developmental period, 24 but can still be selectively reversed by pharmacological 5HT1A receptor blockage later in life suggesting a life-long modulatory involvement of the serotonergic system.…”

“…19 The anxious-depressive phenotype in 5-HTT knockout mice is associated with increased dendritic branching in the 'fear circuit' including the amygdala and limbic cortex. 20 On the other hand, mice with transgenically increased 5-HTT expression appear fearless and explore bright-lit and open spaces more daringly than wild-type animals. 17 Given the importance of early life stressors and their interaction with 5-HTTLPR genotype in the development of psychiatric disorders in humans, it would be of interest to model the interaction of 5-HTT knockout with early life stress in mice.…”