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Mol Brain. 2019 Apr 1;12(1):29. doi: 10.1186/s13041-019-0452-5.

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice.

Author information

1
Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore.
2
Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
3
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
4
Department of Biomedical Engineering, School of Life Science, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Republic of Korea.
5
Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. wonkyung@snu.ac.kr.
6
Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore (NUS) Medical School, 8 College Road, Singapore, 169857, Singapore. shawn.je@duke-nus.edu.sg.
7
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. shawn.je@duke-nus.edu.sg.

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT2AR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT2AR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.

KEYWORDS:

Fluoxetine; Prenatal; Selective serotonin reuptake inhibitor (SSRI); Serotonin (5-HT); Serotonin 2A receptor (5-HT2AR); Social recognition; Working memory

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