Abstract
Rationale
A promoter variant of the serotonin transporter (SERT) gene is known to affect emotional and cognitive regulation. In particular, the “short” allelic variant is implicated in the etiology of multiple neuropsychiatric disorders. Heterozygous (SERT+/−) and homozygous (SERT−/−) SERT mutant mice are valuable tools for understanding the mechanisms of altered SERT levels. Although these genetic effects are well investigated in adulthood, the developmental trajectory of altered SERT levels for behavior has not been investigated.
Objectives
We assessed anxiety-like and cognitive behaviors in SERT mutant mice in early adolescence and adulthood to examine the developmental consequences of reduced SERT levels. Spine density of pyramidal neurons was also measured in corticolimbic brain regions.
Results
Adult SERT−/− mice exhibited increased anxiety-like behavior, but these differences were not observed in early adolescent SERT−/− mice. Conversely, SERT+/− and SERT−/− mice did display higher spontaneous alternation during early adolescence and adulthood. SERT+/− and SERT−/− also exhibited greater neuronal spine densities in the orbitofrontal but not the medial prefrontal cortices. Adult SERT−/− mice also showed an increased spine density in the basolateral amygdala.
Conclusions
Developmental alterations of the serotonergic system caused by genetic inactivation of SERT can have different influences on anxiety-like and cognitive behaviors through early adolescence into adulthood, which may be associated with changes of spine density in the prefrontal cortex and amygdala. The altered maturation of serotonergic systems may lead to specific age-related vulnerabilities to psychopathologies that develop during adolescence.
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Acknowledgments
The authors gratefully thank Drs. Daisuke Suzuki and Yosefu Arime for statistical consultation. This study was supported by a Grant-in-Aid for Health and Labour Science Research (Research on Pharmaceutical and Medical Safety) from MHLW of Japan; by Grants-in-Aid for Core Research for Evolutional Science and Technology (CREST), Global COE Program (Basic and Translational Research Center for Global Brain Science) from MEXT of Japan and through funding from the Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS, USA (GRU and FSH). YS was supported by an Ishidsu Shun Memorial Scholarship. All animal handling and experimental procedures were performed in accordance with the Guidelines for the Care of Laboratory Animals of Tohoku University Graduate School of Medicine (Sendai, Japan).
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Sakakibara, Y., Kasahara, Y., Hall, F.S. et al. Developmental alterations in anxiety and cognitive behavior in serotonin transporter mutant mice. Psychopharmacology 231, 4119–4133 (2014). https://doi.org/10.1007/s00213-014-3554-x
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DOI: https://doi.org/10.1007/s00213-014-3554-x