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Mol Autism. 2018 Apr 10;9:24. doi: 10.1186/s13229-018-0210-z. eCollection 2018.

Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging.

Author information

1
1Mouse Imaging Centre (MICe), Hospital for Sick Children, 25 Orde Street, Toronto, Ontario M5T 3H7 Canada.
2
4Department of Medical Biophysics, University of Toronto, Toronto, ON M5S Canada.
3
3Department of Psychiatry, Vanderbilt University, Nashville, TN 37235 USA.
4
2Department of Pharmacology, Vanderbilt University, Nashville, TN 37235 USA.
5
5Department of Biomedical Science and Brain Institute, Florida Atlantic University, Jupiter, FL 33431 USA.
6
6Department of Psychiatry, Columbia University, New York, NY 10027 USA.

Abstract

Background:

The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied.

Methods:

Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6).

Results:

Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices.

Conclusions:

This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization.

KEYWORDS:

5-HT; 5HTT; Brain; Dorsal raphe; Magnetic resonance imaging; Neurodevelopment; Serotonin; Slc6a4

PMID:
29651330
PMCID:
PMC5894125
DOI:
10.1186/s13229-018-0210-z
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The animal care committees at Vanderbilt University and the Toronto Centre for Phenogenomics approved all these experiments.Not applicableJV has received research funding from Seaside Therapeutics, Novartis, Roche Pharmaceuticals, Forest, Sunovion, and SynapDx and has consulted for or served on advisory boards for Novartis, Roche, and SynapDx. The remaining authors declare no conflicts of interest.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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