Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice.
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.
Wellman
C L
CL
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
Izquierdo
A
A
Garrett
J E
JE
Martin
K P
KP
Carroll
J
J
Millstein
R
R
Lesch
K-P
KP
Murphy
D L
DL
Holmes
A
A
D000223:Adaptation, Psychological / Q000502:physiology*; D000679:Amygdala / Q000166:cytology / Q000378:metabolism; D000818:Animals; D003213:Conditioning, Psychological / Q000502:physiology; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D008032:Limbic System / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism*
D050486:Serotonin Plasma Membrane Transport Proteins