Serotonin receptor regulation as a potential mechanism for sexually dimorphic oxytocin dysregulation in a model of Autism

Edwards, Kimbra A.; Madden, Amanda M. K.; Zup, Susan L.

doi:10.1016/j.brainres.2018.07.020

Cited by 18 publications

(9 citation statements)

References 47 publications

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“…All animal work was performed under the supervision of the University of Massachusetts Boston Institutional Animal Care and Use Committee. Male and female Sprague‐Dawley rats (postnatal day 18, n = 8 male, 6 female; postnatal day 52‐86, n = 7 male, 6 female) were sacrificed and brains fixed with 4% paraformaldehyde as previously described (Edwards, Madden, & Zup, ).…”

Section: Methodsmentioning

confidence: 99%

Age‐dependent sexual dimorphism in hippocampal cornu ammonis‐1 perineuronal net expression in rats

et al. 2019

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Introduction Perineuronal nets (PNNs) are extracellular matrices that encompass parvalbumin‐expressing parvalbumin positive (PVALB+) fast‐spiking inhibitory interneurons where they protect and stabilize afferent synapses. Recent observations that gonadal hormones influence PVALB+ neuron development suggest that PNN regulation may be sexually dimorphic. Sex differences in PNN abundance and complexity have been reported in sexually dimorphic nuclei in zebra finch brains; however, corresponding differences in mammalian brains have not been investigated. Methods In this study we assessed the number of cortical and hippocampal PNNs in juvenile and young adult male and female rats using fluorescent immunohistochemistry for PVALB and the PNN marker Wisteria Floribunda Lectin. Results We report here that PNNs are numerous and well developed in hippocampal cornu ammonis‐1 of adult males but are lower in juvenile and possibly adult females. No significant differences were observed between sexes in cornu ammonis‐3 or adjacent neocortex. There was an observed developmental difference in the neocortex as juveniles had more PVALB+ cells, but fewer PNN+ cells, than adults. Conclusions Because PNNs are integral for several hippocampal‐mediated learning and memory tasks, these observations have potential sex‐dependent translational implications for clinical strategies targeting cognitive dysfunction.

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Section: Methodsmentioning

confidence: 99%

Age‐dependent sexual dimorphism in hippocampal cornu ammonis‐1 perineuronal net expression in rats

et al. 2019

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“…Spine density, another phenotype strongly implicated in autism (Comery et al, 1997; Irwin et al, 2001; Hutsler and Zhang, 2010; Durand et al, 2012; Takuma et al, 2014; Tang et al, 2014; Liu et al, 2017a, b; Soltani et al, 2017), is also affected by testosterone (Hatanaka et al, 2015). Key molecules involved in neurotransmission such as GABA, glutamate, serotonin, and BDNF are all implicated in ASD and modulated by sex hormones (Kim et al, 2016, p. 2; Saghazadeh and Rezaei, 2017; Al-Otaish et al, 2018; Edwards et al, 2018; Ferri et al, 2018; Garbarino et al, 2018; Zieminska et al, 2018). It is not yet clear whether the majority of differences between male and female presentation of ASD arise from differential regulatory actions of sex hormones or from other modifiers, but the presence of a sexually dimorphic phenotype is well established.…”

Section: Modifiers In Asdmentioning

confidence: 99%

Genetic Causes and Modifiers of Autism Spectrum Disorder

Rylaarsdam

Guemez‐Gamboa

2019

Front. Cell. Neurosci.

371

229

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Autism Spectrum Disorder (ASD) is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD is highly genetically heterogeneous and may be caused by both inheritable and de novo gene variations. In the past decade, hundreds of genes have been identified that contribute to the serious deficits in communication, social cognition, and behavior that patients often experience. However, these only account for 10–20% of ASD cases, and patients with similar pathogenic variants may be diagnosed on very different levels of the spectrum. In this review, we will describe the genetic landscape of ASD and discuss how genetic modifiers such as copy number variation, single nucleotide polymorphisms, and epigenetic alterations likely play a key role in modulating the phenotypic spectrum of ASD patients. We also consider how genetic modifiers can alter convergent signaling pathways and lead to impaired neural circuitry formation. Lastly, we review sex-linked modifiers and clinical implications. Further understanding of these mechanisms is crucial for both comprehending ASD and for developing novel therapies.

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“…Guinea pig polyclonal anti-NeuN (1:500; 266004, SYSY) [35], mouse monoclonal anti-GAD67 (1:500; MAB5406, Millipore) [36][37][38], rabbit polyclonal anti-5-HT1A receptor (1:500; ADI-905-741, Enzo) [39] and rabbit polyclonal anti-5-HT2A receptor (1:250; ab66049, Abcam) [40][41][42][43][44] were used as primary antibodies. The primary antibodies used in this study were validated and widely used in previous publications [35][36][37][38][39][40][41][42][43][44]. Alexa Fluor 488 goat anti-rabbit IgG (A11034, Fisher Scientific), Alexa Fluor 555 goat antiguinea pig IgG (A21435, Fisher Scientific) and Alexa Fluor 647 goat anti-mouse IgG (A21236, Fisher Scientific) were used as secondary antibodies.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Expression of serotonin 1A and 2A receptors in molecular- and projection-defined neurons of the mouse insular cortex

Fernandez-Arroyo

et al. 2020

Mol Brain

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The serotonin (5-HT) system is the target of multiple anxiolytics, including Buspirone, which is a partial agonist of the serotonin 1A receptor (5-HT1A). Similarly, ligands of the serotonin 2A receptor (5-HT2A) were shown to alter anxiety level. The 5-HT1A and 2A receptors are widely expressed across the brain, but the target region(s) underlying the influence of those receptors on anxiety remain unknown. Interestingly, recent studies in human and non-human primates have shown that the 5-HT1A and 5-HT2A binding potentials within the insular cortex (insula) are correlated to anxiety. As an initial step to define the function of 5-HT transmission in the insula, we quantified the proportion of specific neuronal populations of the insula expressing 5-HT1A or 5-HT2A. We analyzed seven neural populations, including three defined by a molecular marker (putative glutamate, GABA or parvalbumin), and four defined by their projections to different downstream targets. First, we found that more than 70% of putative glutamatergic neurons, and only 30% of GABAergic neurons express the 5-HT1A. Second, within insular projection neurons, 5-HT1A is highly expressed (75–80%) in the populations targeting one sub-nuclei of the amygdala (central or basolateral), or targeting the rostral or caudal sections of the lateral hypothalamus (LH). Similarly, 70% of putative glutamatergic neurons and only 30% of insular GABAergic neurons contain 5-HT2A. Finally, the 5-HT2A is present in a majority of insula-amygdala and insula-LH projection neurons (73–82%). These observations suggest that most glutamatergic neurons can respond to 5-HT through 5-HT1A or 5-HT2A in the insula, and that 5-HT directly affects a limited number of GABAergic neurons. This study defines a molecular and neuroanatomical map of the 5-HT system within the insular cortex, providing ground knowledge to identify the potential role of serotonergic modulation of selective insular populations in anxiety.

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Serotonin receptor regulation as a potential mechanism for sexually dimorphic oxytocin dysregulation in a model of Autism

Cited by 18 publications

References 47 publications

Age‐dependent sexual dimorphism in hippocampal cornu ammonis‐1 perineuronal net expression in rats

Age‐dependent sexual dimorphism in hippocampal cornu ammonis‐1 perineuronal net expression in rats

Genetic Causes and Modifiers of Autism Spectrum Disorder

Expression of serotonin 1A and 2A receptors in molecular- and projection-defined neurons of the mouse insular cortex

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