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

Yu, Weonjin; Yen, Yi-Chun; Lee, Younghwan; Tan, Siong Kiat; Yang, Xiao; Lokman, Hidayat; Ting, Audrey Khoo Tze Ting; Ganegala, Hasini Easara Wijayabandara; Kwon, Taejoon; Ho, Won‐Kyung; Je, H. Shawn

doi:10.1186/s13041-019-0452-5

Cited by 22 publications

(25 citation statements)

References 58 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another mechanism suggested is the disturbed mPFC excitation/inhibition as determined by a downregulation in NMDAR1 and CaMKIIα expression and an increase in GABAergic interneurons in the mPFC. The changes related to the mPFC excitation/inhibition might again be a compensation for the overall increased prefrontal excitation [223,238]. In support, prenatal fluoxetine exposure caused augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons within the mPFC and led to an increase in the migratory speed of inhibitory cortical interneurons [239].…”

Section: Maternal Ssri Intake Affects Animal Offspring's Brain Circuimentioning

confidence: 89%

“…Bond et al [227] Maloney et al [226] (social preference) Ehrlich et al [218] Khatri et al [205] Olivier et al [209] Rodriguez-Porcel et al [228] Simpson et al [229] Silva et al [222] Yu et al [223] Zimmerberg & Germeyan [224] Houwing et al [230] Gemmel et al [150] (normalised stress effect) Gemmel et al [160] (irrespective of stress effect) Ko et al [206] Maloney et al [226] (social interaction) Meyer et al [221] Svirsky et al [231] Zaidan et al [232] A few studies investigated the effects of gestational SSRI exposure on the 5-HT system of the offspring. Offspring of pregnant mice that were perinatally treated with fluoxetine and sertraline or prenatally with escitalopram exhibited whole brain decreases in MAOA expression and whole brain increases in cortical expression of TPH2, 5-HTT, and 5-HT 1A/2A/C receptors [218,221,227].…”

Section: Decreased Social Behaviormentioning

confidence: 99%

“…A few studies suggest a link between presynaptic 5-HT 1A activity and social interaction or depressive-like behavior and between hippocampal neurogenesis and anxiety-like behavior [210,213,218]. Other studies propose the decrease in mPFC dendritic complexity as one of the underlying mechanisms in decreased social recognition and increases in anxiety-like and depressive-like behaviors [7,206,216,223]. Neonatal fluoxetine did not affect adult hippocampal neurogenesis but normalized decreased hippocampal neurogenesis evident in prenatally restraint-stress adolescent offspring [162,213].…”

Section: Maternal Ssri Intake Affects Animal Offspring's Brain Circuimentioning

confidence: 99%

See 2 more Smart Citations

Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

Hanswijk

Spoelder

Shan

et al. 2020

IJMS

View full text Add to dashboard Cite

Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other’s impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.

show abstract

Section: Maternal Ssri Intake Affects Animal Offspring's Brain Circuimentioning

confidence: 89%

Section: Decreased Social Behaviormentioning

confidence: 99%

Section: Maternal Ssri Intake Affects Animal Offspring's Brain Circuimentioning

confidence: 99%

See 1 more Smart Citation

Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

Hanswijk

Spoelder

Shan

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…DES and FLX have distinct mechanism of action, while the former inhibits NE reuptake 83,84 , the second selectively inhibits serotonin reuptake 85,86 . FLX effect in increasing neurogenesis is well grounded in the literature [87][88][89] .…”

Section: Discussionmentioning

confidence: 99%

Pro-neurogenic effect of fluoxetine in the olfactory bulb is concomitant to improvements in social memory and depressive-like behavior of socially isolated mice

Medeiros

et al. 2020

Transl Psychiatry

View full text Add to dashboard Cite

Although loneliness is a human experience, it can be estimated in laboratory animals deprived from physical contact with conspecifics. Rodents under social isolation (SI) tend to develop emotional distress and cognitive impairment. However, it is still to be determined whether those conditions present a common neural mechanism. Here, we conducted a series of behavioral, morphological, and neurochemical analyses in adult mice that underwent to 1 week of SI. We observed that SI mice display a depressive-like state that can be prevented by enriched environment, and the antidepressants fluoxetine (FLX) and desipramine (DES). Interestingly, chronic administration of FLX, but not DES, was able to counteract the deleterious effect of SI on social memory. We also analyzed cell proliferation, neurogenesis, and astrogenesis after the treatment with antidepressants. Our results showed that the olfactory bulb (OB) was the neurogenic niche with the highest increase in neurogenesis after the treatment with FLX. Considering that after FLX treatment social memory was rescued and depressive-like behavior decreased, we propose neurogenesis in the OB as a possible mechanism to unify the FLX ability to counteract the deleterious effect of SI.

show abstract

“…Furthermore, plasma fluoxetine transfer from mother to pup was around 83%. Despite these behavioral studies, there are almost no studies looking directly at the effects on neural circuit function of early SSRI exposure (Yu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Early developmental exposure to Fluoxetine and Citalopram results in different neurodevelopmental outcomes

Liu

Garcia

Park

et al. 2019

Preprint

View full text Add to dashboard Cite

Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for prenatal depression, there exists controversy over the adverse effects of SSRI use on fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we directly investigated the outcomes of exposure to widely-used SSRIs fluoxetine and citalopram on the developing nervous system of Xenopus laevis tadpoles, using an integrative experimental approach. We exposed tadpoles to low doses of citalopram and fluoxetine during a critical developmental period and found that the different groups of tadpoles displayed opposing behavioral effects. While both groups showed reduced schooling behavior, the fluoxetine group showed increased seizure susceptibility and reduced startle habituation. In contrast, the citalopram treated tadpoles had decreased seizure susceptibility and increased habituation. Both groups had abnormal dendritic morphology in the optic tectum, a brain area important for all three behaviors tested.Whole-cell electrophysiological recordings of tectal neurons showed no differences in synaptic function across groups; however, tectal cells from fluoxetine-treated tadpoles had decreased voltage gated K+ currents while cells in the citalopram group had increased K+ currents. Both the behavior and electrophysiological findings indicate that cells and circuits in the fluoxetine treated optic tecta are hyperexcitable, while the citalopram group exhibits decreased excitability. Taken all together, these results show that early developmental exposure to SSRIs is sufficient to induce neurodevelopmental effects, however these effects can be complex and vary depending on the SSRI used.This may explain some of the discrepancies across human studies, and further underscores the importance of serotonergic signaling for the developing nervous system.

show abstract

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

Cited by 22 publications

References 58 publications

Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

Pro-neurogenic effect of fluoxetine in the olfactory bulb is concomitant to improvements in social memory and depressive-like behavior of socially isolated mice

Early developmental exposure to Fluoxetine and Citalopram results in different neurodevelopmental outcomes

Contact Info

Product

Resources

About