Subregion‐specific decreases in hippocampal serotonin transporter protein expression and function associated with endophenotypes of depression

Tang, Man; He, Tao; Sun, Xiao; Meng, Qingyan; Diao, Yun-Peng; Lei, Jie-Yu; He, Xin; Chen, Lei; Sang, Xiu-Bo; Zhao, Shulei

doi:10.1002/hipo.22242

Cited by 18 publications

(23 citation statements)

References 79 publications

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“…Since FGF22 is required for normal excitatory synapse development in the hippocampus, and the hippocampus has been implicated in affective behaviors modeled by the forced swim and tail suspension tests (28, 29), our results are consistent with the hypothesis that loss of excitatory synapses in the hippocampus is responsible for the altered behaviors observed in FGF22KO mice, including a passive style of coping with stress and anhedonia. Of course, it is also possible that there are other brain regions involved in the behaviors we observed, such as the prefrontal cortex (30-32), and we are currently investigating the neural circuits that may be involved in the behavioral manifestations of FGF22 deletion.…”

Section: Discussionsupporting

confidence: 87%

“…In this test, animals are provided with both water and 2% sucrose solution for several days to measure the degree of their preference for sucrose over water. Typically, mice prefer sucrose at a very high ratio (28). Using a separate cohort of experiment-naïve mice, we observed that WT mice demonstrate a significant preference for sucrose over water, whereas FGF22KO animals prefer sucrose to a lower extent, consistent with lack of pleasure-motivated behavior or anhedonia (Student's unpaired two-tailed t -test, t(29)=4.66, p<0.0001) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice

Williams

Yee

Smith

et al. 2016

Behavioural Brain Research

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Specific growth factors induce formation and differentiation of excitatory and inhibitory synapses, and are essential for brain development and function. Fibroblast growth factor 22 (FGF22) is important for specifying excitatory synapses during development, including in the hippocampus. Mice with a genetic deletion of FGF22 (FGF22KO) during development subsequently have fewer hippocampal excitatory synapses in adulthood. As a result, FGF22KO mice are resistant to epileptic seizure induction. In addition to playing a key role in learning, the hippocampus is known to mediate mood and anxiety. Here, we explored whether loss of FGF22 alters affective, anxiety or social cognitive behaviors in mice. We found that relative to control mice, FGF22KO mice display longer duration of floating and decreased latency to float in the forced swim test, increased immobility in the tail suspension test, and decreased preference for sucrose in the sucrose preference test, which are all suggestive of a depressive-like phenotype. No differences were observed between control and FGF22KO mice in other behavioral assays, including motor, anxiety, or social cognitive tests. These results suggest a novel role for FGF22 specifically in affective behaviors.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice

Williams

Yee

Smith

et al. 2016

Behavioural Brain Research

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“…The 5-HT system is highly interactive with other biological systems. Being one of the brain areas implicated in MDD, the hippocampus may have a particular role in the interactions between the 5-HT system and the hypothalamic-pituitary-adrenal (HPA) axis [ 27 , 45 ]. Lower mRNA expression of cortisol-inducible genes, which can be seen as a marker for a blunted cortisol response, was previously found to be associated with smaller hippocampal volumes in MDD patients [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation of the Serotonin Transporter Gene in Peripheral Cells and Stress-Related Changes in Hippocampal Volume: A Study in Depressed Patients and Healthy Controls

et al. 2015

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Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD) (23 females) and 36 matched healthy controls (21 females) were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology.

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“…data to the Michaelis-Menten equation as previously described (Tang et al, 2014). Values of both parameters are shown in Table 2.…”

Section: Strain Differences In 5-htt Protein Expression In Each Hippomentioning

confidence: 99%

“…For synaptosomal 5-HT uptake, V max is positively related to the total number, and K m is negatively related to the uptake efficiency, of the membrane-bound 5-HTT, respectively (Ansah et al, 2003;Zhu et al, 2010;Hagan et al, 2012;Tang et al, 2014). Our data showed that DBA mice showed a higher V max and a lower K m , indicating that the mice not only had more membrane-bound 5-HTT, but also had higher uptake efficiency in all three hippocampal subregions compared to the other three mouse strains (Fig.…”

Section: Strain Differences In 5-htt Protein Expression In Each Hippomentioning

confidence: 99%

Immobility responses between mouse strains correlate with distinct hippocampal serotonin transporter protein expression and function

Tang

Meng³

et al. 2014

Int. J. Neuropsychopharm.

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Mouse strain differences in immobility and in sensitivity to antidepressants have been observed in the forced swimming test (FST) and the tail suspension test (TST). However, the neurotransmitter systems and neural substrates that contribute to these differences remain unknown. To investigate the role of the hippocampal serotonin transporter (5-HTT), we measured baseline immobility and the immobility responses to fluoxetine (FLX) in the FST and the TST in male CD-1, C57BL/6, DBA and BALB/c mice. We observed strain differences in baseline immobility time, with CD-1 mice showing the longest and DBA mice showing the shortest. In contrast, DBA and BALB/c mice showed the highest sensitivity to FLX, whereas CD-1 and C57BL/6 mice showed the lowest sensitivity. Also we found strain differences in both the total 5-HTT protein level and the membrane-bound 5-HTT level (estimated by V max) as follows: DBA>BALB/c>CD-1=C57BL/6. The uptake efficiency of the membrane-bound 5-HTT (estimated by 1/K m) was highest in DBA and BALB/c mice and lowest in CD-1 and C57BL/6 mice. A correlation analysis of subregions within the hippocampus revealed that immobility time was negatively correlated with V max and positively correlated with K m in the hippocampus. Therefore a higher uptake capacity of the membrane-bound 5-HTT in the hippocampus was associated with lower baseline immobility and greater sensitivity to FLX. These results suggest that alterations in hippocampal 5-HTT activity may contribute to mouse strain differences in the FST and the TST.

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Subregion‐specific decreases in hippocampal serotonin transporter protein expression and function associated with endophenotypes of depression

Cited by 18 publications

References 79 publications

Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice

Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice

DNA Methylation of the Serotonin Transporter Gene in Peripheral Cells and Stress-Related Changes in Hippocampal Volume: A Study in Depressed Patients and Healthy Controls

Immobility responses between mouse strains correlate with distinct hippocampal serotonin transporter protein expression and function

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