Genetic Knockout of the Serotonin Reuptake Transporter Results in the Reduction of Dendritic Spines in In vitro Rat Cortical Neuronal Culture

Chaji, Daniel; Venkatesh, Varun; Shirao, Tomoaki; Day, Darren J.; Ellenbroek, Bart A.

doi:10.1007/s12031-020-01764-9

Cited by 9 publications

(12 citation statements)

References 61 publications

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“…In PD, aberrant soluble oligomeric conformations of α-Syn mediate the disruption of cellular homeostasis and eventual death [ 339 ]. Additionally, α-Syn interacts with serotonin transporter activity by sequestrating it from the cellular membrane [ 340 ], which exerts deleterious effects on the structural plasticity [ 341 ]. Thus, dysregulations of dendritic spines in the hippocampus of the PD brain seem to be associated with interactions between several factors (neurotransmitters and abnormal protein aggregates), which contributes to the pathophysiology in both preclinical and clinical PD.…”

Section: Hippocampal Structural Plasticity In Neurodegenerative Diseasesmentioning

confidence: 99%

Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

Weerasinghe-Mudiyanselage

Ang

Kang

et al. 2022

IJMS

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Neuroplasticity is the capacity of neural networks in the brain to alter through development and rearrangement. It can be classified as structural and functional plasticity. The hippocampus is more susceptible to neuroplasticity as compared to other brain regions. Structural modifications in the hippocampus underpin several neurodegenerative diseases that exhibit cognitive and emotional dysregulation. This article reviews the findings of several preclinical and clinical studies about the role of structural plasticity in the hippocampus in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. In this study, literature was surveyed using Google Scholar, PubMed, Web of Science, and Scopus, to review the mechanisms that underlie the alterations in the structural plasticity of the hippocampus in neurodegenerative diseases. This review summarizes the role of structural plasticity in the hippocampus for the etiopathogenesis of neurodegenerative diseases and identifies the current focus and gaps in knowledge about hippocampal dysfunctions. Ultimately, this information will be useful to propel future mechanistic and therapeutic research in neurodegenerative diseases.

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Section: Hippocampal Structural Plasticity In Neurodegenerative Diseasesmentioning

confidence: 99%

Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

Weerasinghe-Mudiyanselage

Ang

Kang

et al. 2022

IJMS

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“…Growing evidence suggests that serotonergic signaling and mitochondrial dysfunction may be linked in the pathophysiology of neuropsychiatric disorders. Mitochondrial biogenesis is regulated by signaling through specific 5‐HT receptors (Chaji et al., 2021; Gibbs et al., 2018; Gressier et al., 2016; Lesch et al., 1996; Simmons et al., 2019) with signaling through the 5‐HT 2A receptor leading to increased expression of the transcriptional coactivator peroxisome proliferator‐activated receptor gamma cofactor 1‐alpha (PGC‐1α), in cultured cortical neurons, resulting in increased oxygen consumption, ATP production, mtDNA mass, and antioxidant capacity (Fanibunda et al., 2019). 5HT 1F receptor agonists have similarly been shown to induce mitochondrial biogenesis in rodent studies of kidney injury, spinal cord injury, and Parkinson's disease (Fanibunda et al., 2019; Gibbs et al., 2018; Scholpa et al., 2018; Simmons et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

“…The 5‐HTTLPR S‐allele (S/S genotype) results in around a 50% reduction in SERT expression and an increased likelihood of developing depressive and anxiety disorders, particularly in women (Gressier et al., 2016; Lesch et al., 1996). The SERT knockout rat has been extensively characterized (Chaji et al., 2021; Homberg et al., 2008; Homberg, Olivier, et al., 2007; Olivier et al., 2008; Smits et al., 2006) and is a valuable model for studying serotonergic signaling, with the heterozygous animals being proposed as a good model of the low expressing human S/S variant (Homberg, Olivier, et al., 2007; Olivier et al., 2008). Given the importance of serotonergic signaling in mitochondrial biogenesis and neuropsychiatric disorders, we sought to determine whether there were differences in mitochondrial abundance and mRNA expression of the mitochondrial respiratory complex subunits in the frontal cortex (FC) and cerebellum (Cb) of SERT knockout wild‐type (WT) and heterozygous (HET) rats.…”

Section: Introductionmentioning

confidence: 99%

The serotonin reuptake transporter modulates mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner

Thorne

Ellenbroek

Day

2022

J of Neuroscience Research

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Neuropsychiatric and neurodevelopmental disorders such as major depressive disorder (MDD) and autism spectrum disorder (ASD) are complex conditions attributed to both genetic and environmental factors. There is a growing body of evidence showing that serotonergic signaling and mitochondrial dysfunction contribute to the pathophysiology of these disorders and are linked as signaling through specific serotonin(5-HT) receptors drives mitochondrial biogenesis. The serotonin transporter (SERT) is important in these disorders as it regulates synaptic serotonin and therapeutically is the target of selective serotonin reuptake inhibitors which are a major class of anti-depressant drug. Human allelic variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) such as the S/S variant, are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. Using a rat model that is haploinsufficient for SERT and displays reduced SERT expression similar to the human S/S variant, we demonstrate that reduced SERT expression modulates mitochondrial copy number and expression of respiratory chain electron transfer components in the brain. In the frontal cortex, genotype-related trends were opposing for males and females, such that reduced SERT expression led to increased expression of the Complex I subunit mt-Nd1 in males but reduced expression in females. Our findings suggest that SERT expression and serotonergic signaling have a role in regulating mitochondrial biogenesis and adenosine triphosphate (ATP) production in the brain. We speculate that the sexual dimorphism in mitochondrial abundance and gene expression contributes to the sex bias found in the incidence of neuropsychiatric disorders such as MDD and ASD.

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“…Adapted from Liu et al (2013a) 5-HT depletion and 5-HT1A antagonism both decrease dendritic spines, and this is accompanied by a decrease in synaptic density (Faber & Haring, 1999). Similarly, new research from our own laboratory found that neurons in primary cell cultures showed a gene dosage dependent decrease in spine density, with homozygous SERT knockouts having the smallest, and WT, the largest number of spines (Chaji, Venkatesh, Shirao, Day & Ellenbroek, 2021). On the other hand, antidepressant treatment increases synapses in the hippocampal CA1 region (Chen, Madsen, Wegener & Nyengaard, 2010).…”

Section: Figurementioning

confidence: 99%

“…Several studies do show that newly generated neurons are functional additions to hippocampal circuitry as they form axonal projections, make synaptic connections and have the same electrophysiological characteristics of neighbouring mature cells in neurotypical animals (Markakis & Gage, 1999;van Praag et al, 2002). However, at least in cell cultures, HOM rats have reduced spine formation (Chaji et al 2021). Thus, it is conceivable that even if more newborn cells develop into more neurons in HET and HOM offspring, they may not correctly synapse onto their postsynaptic targets.…”

Section: Theoretical Implicationsmentioning

confidence: 99%

Neurogenic Plasticity in a Serotonin Transporter Knockout Model: Effects of Maternal and Offspring Genotype

Tapnikar¹

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<p>Major depressive disorder (MDD) is debilitating mental disorder that is increasing in prevalence. Many theories have tried to explain the aetiology of depression including the classic monoamine deficiency hypothesis and the newer neurogenic hypothesis. The finding that selective serotonin transporter inhibitors (SSRIs) work by increasing extracellular serotonin levels in the brain and have antidepressant effects has formed the basis of the most widely accepted theory of depression, the monoamine hypothesis. However, a genetic reduction in human and animal serotonin reuptake transporters, which also increases extracellular serotonin, is associated with depressive symptomology. This paradox is not explained by the monoamine hypothesis. The key difference between these two scenarios is that genetically induced increases in serotonin occur from development onward, while SSRIs increase serotonin only in adulthood. Furthermore, SSRIs typically take several weeks to confer a therapeutic effect. This finding has led to the hypothesis that, rather than acute monoamine-increasing effects, it is the downstream effects of such increases on neurogenesis and neural plasticity which confer antidepressant effects. To further elucidate the neurobiology of depression, this study sought to examine the effects of genetically increasing serotonin on early postnatal neurogenesis in a serotonin knockout rat model using BrdU immunohistochemistry. We examined both the offspring and maternal genotype effects. We found that SERT-/- offspring had the highest levels of neurogenesis compared with SERT+/- and SERT+/+ at postnatal day 7. In addition we found a maternal genotype effect with SERT+/+ offspring born and reared by SERT+/- mothers having lower neurogenesis compared to SERT+/+ offspring from SERT+/+ mothers. The potential effects of maternal caregiving, neuroplasticity in altered mood and stress responses and the role of 5-HT receptors are discussed.</p>

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Genetic Knockout of the Serotonin Reuptake Transporter Results in the Reduction of Dendritic Spines in In vitro Rat Cortical Neuronal Culture

Cited by 9 publications

References 61 publications

Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

The serotonin reuptake transporter modulates mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner

Neurogenic Plasticity in a Serotonin Transporter Knockout Model: Effects of Maternal and Offspring Genotype

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