Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

Muller, Christopher L.; Anacker, Allison M.J.; Rogers, Tiffany D.; Goeden, Nick; Keller, Elizabeth H; Forsberg, C. Gunnar; Kerr, Travis M.; Wender, Carly L. A.; Anderson, George M.; Stanwood, Gregg D.; Blakely, Randy D.; Bonnin, Alexandre; Veenstra‐VanderWeele, Jeremy

doi:10.1038/npp.2016.166

Cited by 57 publications

(47 citation statements)

References 53 publications

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“…Through the tube test and other tests of social behaviors in rodents, connections between the PFC and amygdala have been identified as regulating social behavior, as have thalamocortical connections [Felix‐Ortiz, Burgos‐Robles, Bhagat, Leppla, & Tye, ; Ferguson & Gao, ]. This circuitry is dysregulated in mouse models of ASD [Ellegood et al, ; Muller et al, ], and these general findings correspond with evidence of dysregulated activity and connectivity of ASD patients [Green, Hernandez, Bookheimer, & Dapretto, ; see meta‐analysis by Patriquin, DeRamus, Libero, Laird, and Kana, ]. Dominance behavior and social hierarchy are governed by multiple neuronal circuits, but manipulations of the PFC have demonstrated causal effects on dominance behavior.…”

Section: Discussionmentioning

confidence: 88%

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice

et al. 2019

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The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2 +/− mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors. However, KCC2 +/− mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild-type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2 +/− mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism-like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism-related behavioral phenotypes.Lay Summary: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism-related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism-like behaviors.

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Section: Discussionmentioning

confidence: 88%

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice

et al. 2019

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“…It could be concluded that differences in various tissues/organs concurrently contribute to total body weight differences between 5HT sublines. It is known that 5HT has an important developmental role as a trophic/growth factor (Gaspar et al, 2003) and that maternal 5HT activity impacts fetal development (Côté et al, 2007;Muller et al, 2017). Hence, increased birth weight of high-5HT pups may indicate that maternal high 5HT tone stimulated their in utero growth.…”

Section: Discussionmentioning

confidence: 99%

Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis

et al. 2020

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Central and peripheral pools of biogenic monoamine serotonin (5-hydroxytryptamine [5HT]) exert opposite effects on the body weight regulation: increase in brain 5HT activity is expected to decrease body weight, whereas increase in peripheral 5HT activity will increase body weight and adiposity. In a genetic model of rats with constitutionally highor low-5HT homeostasis (hyperserotonergic/hyposerotonergic rats), we have studied how individual differences in endogenous 5HT tone modulate net energy balance of the organism. The high-5HT and low-5HT sublines of the model were developed by selective breeding toward extreme platelet activities of 5HT transporter, a key molecule determining 5HT bioavailability/activity. In animals from high-5HT and low-5HT sublines, we assessed physiological characteristics associated with body weight homeostasis and expression profile of a large scale of body weight-regulating genes in hypothalamus, a major brain region controlling energy balance. Results showed that under standard chow diet animals from the high-5HT subline, as compared to low-5HT animals, have lifelong increased body weight (by 12%), higher absolute daily food intake (by 9%), and different pattern of fat distribution (larger amount of white adipose tissue and lower amount of brown adipose tissue). A large number of body weight-regulating hypothalamic genes were analyzed for their mRNA expression: 24 genes by reverse transcription-quantitative polymerase chain reaction (n = 9-10 rats/subline) including neuropeptides and their receptors, growth factors, transcriptional factors, and receptors for peripheral signals, and a total of 84 genes of various classes by polymerase chain reaction array (pools of six rats/subline). Only few genes showed significant differences in mRNA expression levels between 5HT sublines (e.g. neuropeptide Y receptor, fibroblast growth factor 10), but high-5HT animals displayed a clear trend to upregulation of mRNAs for a number of orexigenic signaling peptides, their receptors, and other molecules with orexigenic activity. Receptors for peripheral signals (leptin, insulin) and molecules in their downstream signaling were not altered, indicating no changes in central insulin/leptin resistance. At the protein level, there were no differences in the Frontiers in Neuroscience | www.frontiersin.org 1 March 2020 | Volume 14 | Article 219 Kesić et al. Serotonin and Body Weight Regulationcontent of hypothalamic leptin receptor between 5HT sublines, but significant sex and age effects were observed. Results show that higher constitutive/individual 5HT tone favors higher body weight and adiposity probably due to concurrent upregulation of several hypothalamic orexigenic pathways.

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“…Perinatal SSRIs can at times protect against the effect of maternal stress, have effects independent of maternal stress, and have effects on offspring that are sexually differentiated. The effects of perinatal SSRIs on hippocampal plasticity may be both direct, due to perinatal drug exposure, and indirect, with effects mediated by maternal care as well as SSRI effects on the placenta [17, [82][83][84]. Apart from effects on hippocampal plasticity, a growing body of literature shows that perinatal exposure to SSRIs affects a number of neuroendocrine systems and neurobehavioral outcomes which may be linked to the hippocampus.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Perinatal SSRI medications and offspring hippocampal plasticity: interaction with maternal stress and sex

Pawluski

Gemmel

2018

Hormones

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There is growing use of selective serotonin reuptake inhibitor antidepressant (SSRI) medications during the perinatal period to treat maternal affective disorders. Perinatal SSRI exposure can have a long-term impact on offspring neuroplasticity and behavioral development that remains to be fully elucidated. This mini-review will summarize what is known about the effects of perinatal SSRIs on plasticity in the developing hippocampus, taking into account the role that maternal stress and depression may have. Emerging clinical findings and research in animal models will be discussed. In addition, sexually differentiated effects will be highlighted, as recent work shows that male offspring are often more sensitive to the effects of maternal stress, whereas female offspring can be more sensitive to perinatal SSRIs. Potential mechanisms behind these changes and aims for future research will also be discussed. Understanding the impact of perinatal SSRIs on neuroplasticity will provide better insight into the long-term effects of such medications on the health and well-being of both mother and child and may improve therapeutic approaches for maternal mood disorders during the perinatal period.

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Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

Cited by 57 publications

References 53 publications

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice

Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis

Perinatal SSRI medications and offspring hippocampal plasticity: interaction with maternal stress and sex

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