Brain acetylcholine and choline concentrations and dynamics in a murine model of the Fragile X syndrome: Age, sex and region-specific changes

Scremin, Oscar U.; Roch, Margaret; Norman, Kevin J.; Djazayeri, Shima; Liu, Y. Y.

doi:10.1016/j.neuroscience.2015.06.036

Cited by 14 publications

(11 citation statements)

References 55 publications

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“…The female Fmr1 KO mice used here contain two alleles of the Fmr1 KO, one on each X-chromosome. Male and female Fmr1 KO mice show differences in behavioral measures ( Nolan et al, 2017 ), vocalization production ( Reynolds et al, 2016 ), and neurophysiology ( Giráldez-Pérez et al, 2013 ; Lokanga et al, 2014 ; Scremin et al, 2015 ), but other studies showed similar behaviors between the sexes ( Ding et al, 2014 ). We found that the auditory brainstem phenotypes we observed did not differ between males and females, suggesting predominantly common molecular mechanisms that are not selectively altered by the mutation.…”

Section: Discussionmentioning

confidence: 93%

Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei ofFmr1Knockout Mice

Rotschafer

Cramer

2017

eNeuro

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Fragile X syndrome (FXS), the most common monogenic cause of autism, is often associated with hypersensitivity to sound. Several studies have shown abnormalities in the auditory brainstem in FXS; however, the emergence of these auditory phenotypes during development has not been described. Here, we investigated the development of phenotypes in FXS model [Fmr1 knockout (KO)] mice in the ventral cochlear nucleus (VCN), medial nucleus of the trapezoid body (MNTB), and lateral superior olive (LSO). We studied features of the brainstem known to be altered in FXS or Fmr1 KO mice, including cell size and expression of markers for excitatory (VGLUT) and inhibitory (VGAT) synapses. We found that cell size was reduced in the nuclei with different time courses. VCN cell size is normal until after hearing onset, while MNTB and LSO show decreases earlier. VGAT expression was elevated relative to VGLUT in the Fmr1 KO mouse MNTB by P6, before hearing onset. Because glial cells influence development and are altered in FXS, we investigated their emergence in the developing Fmr1 KO brainstem. The number of microglia developed normally in all three nuclei in Fmr1 KO mice, but we found elevated numbers of astrocytes in Fmr1 KO in VCN and LSO at P14. The results indicate that some phenotypes are evident before spontaneous or auditory activity, while others emerge later, and suggest that Fmr1 acts at multiple sites and time points in auditory system development.

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Section: Discussionmentioning

confidence: 93%

Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei ofFmr1Knockout Mice

Rotschafer

Cramer

2017

eNeuro

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“…NPCs were grown in custom choline-free neurobasal medium, supplemented with 2 mM L-glutamine and B27 supplement without vitamin A (all from Thermo Fisher Scientific, Waltham, MA, USA). Choline chloride (MilliporeSigma, Burlington, MA, USA), dissolved in PBS and sterile filtered, was added to culture medium to final concentrations of 7 mM (LC) or 70 mM (AC) (25). For monolayer cultures, neurospheres were dissociated and plated in 24-well glass-bottom plates (MatTek, Ashland, MA, USA), precoated with polyornithine (MilliporeSigma) and fibronectin (MilliporeSigma).…”

Section: Neural Progenitor Cell Culturementioning

confidence: 99%

MicroRNA‐129‐5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex

et al. 2018

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Choline availability modulates neurogenesis and cerebral cortex development through the regulation of neural progenitor cell (NPC) proliferative and differentiation capacity. In this study, we demonstrated that cortical NPC self‐renewal is controlled by choline via the expression of a microRNA (miR‐129‐5p), whose role in the developing brain has not been examined, and which, in turn, inhibits synthesis of the epidermal growth factor receptor (EGFR) protein. Specifically, we found that low choline (LC) availability led to the upregulation of miR‐129‐5p expression in cortical NPCs in vitro and in vivo, causing the downregulation of EGFR and thereby disrupting NPC self‐renewal and cortical neurogenesis. Furthermore, in response to LC availability, methylation potential (the S‐adenosylmethionine:S‐adenosylhomocysteine ratio) in the developing brain was reduced. Restoring methylation potential in LC cortical NPCs led to the re‐establishment of normal miR‐129‐5p expression. We concluded that inhibiting miR‐129‐5p function and restoring EGFR protein levels in vivo is sufficient to reverse LC‐induced defects in cortical NPC self‐renewal. For the first time, to our knowledge, we have identified the molecular links that explain how a change in the availability of the diet metabolite choline impacts the essential cellular processes underlying brain development.—Trujillo‐Gonzalez, I., Wang, Y., Friday, W. B., Vickers, K. C., Toth, C. L., Molina‐Torres, L., Surzenko, N., Zeisel, S. H. MicroRNA‐129‐5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex. FASEB J. 33, 3601–3612 (2019). http://www.fasebj.org

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“…It has been shown that the fragile X mental retardation 1 ( Fmr1 ) gene that encodes fragile X mental retardation protein (FMRP), regulates the morphology of dendritic spines (Grossman et al, 2006a, Grossman et al, 2006b). In addition, deletion of the Fmr1 gene is associated with increased dendritic spine density and cholinergic deficits in hippocampus (Comery et al, 1997, Grossman et al, 2010, Ivanco and Greenough, 2002, Scharkowski et al, 2017, D’Antuono et al, 2003, Scremin et al, 2015). We reported previously that AIE exposure decreases global H3K9 acetylation in the hippocampus due to increased activity of histone deacetylases (HDAC) and decreases neurogenesis markers in adulthood (Sakharkar et al, 2016), and, as noted above, there is evidence of decreased cholinergic input to the hippocampal formation after AIE (Swartzwelder et al, 2015, Boutros et al, 2014, Vetreno et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure

Mulholland¹,

Teppen

Miller

et al. 2018

Alcoholism Clin & Exp Res

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These findings indicate that AIE produces long-lasting decreases in dendritic spine density and changes in Fmr1 gene expression in the hippocampal formation, suggesting morphological and epigenetic mechanisms underlying previously reported behavioral deficits after AIE. The reversal of these effects by subchronic, post-AIE donepezil treatment indicates that these AIE effects can be reversed by up-regulating cholinergic function.

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Brain acetylcholine and choline concentrations and dynamics in a murine model of the Fragile X syndrome: Age, sex and region-specific changes

Cited by 14 publications

References 55 publications

Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei ofFmr1Knockout Mice

Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei ofFmr1Knockout Mice

MicroRNA‐129‐5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex

Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure

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