Sexually dimorphic patterns in electroencephalography power spectrum and autism-related behaviors in a rat model of fragile X syndrome

Wong, Hayes; Hooper, Alexander W.M.; Niibori, Yosuke; Lee, Shiron J.; Hategan, Luca A.; Zhang, Liang; Karumuthil‐Melethil, Subha; Till, Sally M.; Kind, P.; Danos, Olivier; Bruder, Joseph T.; Hampson, David R.

doi:10.1016/j.nbd.2020.105118

Cited by 19 publications

(56 citation statements)

References 53 publications

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“…Taken together, the current study demonstrates that activation of either mAChR or mGluR is sufficient to mimic the aberrant increase in the gamma oscillations observed in the hippocampus of the FMR1 KO mice in vivo. It should be noted that the increase in gamma oscillation power has also been observed in numerous cortical areas including the auditory, somatosensory, frontal and temporal cortex of the FMR1 KO mice (Jonak et al, 2020;Lovelace et al, 2020Lovelace et al, , 2018Pirbhoy et al, 2020;Wen et al, 2019;Wong et al, 2020). Whether these oscillatory alterations can be mimicked using pharmacologically-induced gamma oscillations in cortical slice preparations (Steullet et al, 2014) needs to be investigated in future.…”

Section: Discussionmentioning

confidence: 98%

“…While the molecular and cellular mechanisms underlying FXS have been extensively studied in rodent models, systematic investigation of behaviorally-relevant neurophysiological oscillations as mesoscopic biomarkers for FXS has only recently accelerated (Arbab et al, 2018;Boone et al, 2018;Dvorak et al, 2018;Jonak et al, 2020;Lovelace et al, 2020Lovelace et al, , 2018Pirbhoy et al, 2020;Radwan et al, 2016;Wen et al, 2019;Wong et al, 2020). Of note, the most striking and converging finding from studies using FMR1 KO mouse model is the gamma-range (30-80 Hz) oscillopathy observed in distinct cortical regions (Jonak et al, 2020;Lovelace et al, 2020Lovelace et al, , 2018Pirbhoy et al, 2020;Wen et al, 2019;Wong et al, 2020) and hippocampus (Arbab et al, 2018;Boone et al, 2018;Dvorak et al, 2018;Radwan et al, 2016). Elevated gamma oscillations appear to be present during diverse behavioral stages including active exploration, rest and sleep (Arbab et al, 2018;Boone et al, 2018;Lovelace et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome

Pollali

Hollnagel

Çalışkan

2021

Preprint

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Fragile X syndrome (FXS) is the most common inherited form of intellectual disability arising from the loss of fragile X mental retardation protein (FMRP), a protein that plays a central role in neuronal function and plasticity. FXS patients show sensory hypersensitivity, hyperarousal and hippocampus-dependent learning deficits that can be recapitulated in the FMR1 KO mice. Enhanced metabotropic glutamate receptor (mGluR) signaling and muscarinic acetylcholine receptor (mAChR) signaling in the FMR1 KO mouse are implicated as the primary causes of the disease pathogenesis. Furthermore, glutamatergic kainate receptor (KAR) function is reduced in the cortex of the FMR1 KO mice. Of note, activation of these signaling pathways leads to slow gamma-range oscillations in the hippocampus in vitro and abnormal gamma oscillations have been reported in FMR1 KO mice and patients with FXS. Thus, we hypothesized that aberrant activation of these receptors leads to the observed gamma oscillopathy. We recorded gamma oscillations induced by either cholinergic agonist carbachol (CCh), mGluR1/5 agonist Dihydroxyphenylglycine (DHPG) or ionotropic glutamatergic agonist KA from the hippocampal CA3 in WT and FMR1 KO mice in vitro. We show a specific increase in the power of DHPG- and CCh-induced gamma oscillations and reduction in the synchronicity of gamma oscillations induced by KA. We further elucidate an aberrant spiking activity during CCh-induced and kainate-induced gamma oscillations which may underlie the altered gamma oscillation synchronization in the FMR1 KO mice. Last, we also noted a reduced incidence of spontaneously-occurring hippocampal sharp wave-ripple events. Our study provides further evidence for aberrant hippocampal rhythms in the FMR1 KO mice and identifies potential signaling pathways underlying gamma band oscillopathy in FXS.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome

Pollali

Hollnagel

Çalışkan

2021

Preprint

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“…13,14 We recently characterized the phenotype of a fragile X KO rat in which an emphasis was placed on comparing male and female KO rats and assessing behavioral parameters that could be potentially translatable to clinical studies in humans. 15 The present study is the first to assess viral vector gene therapy in the Fmr1 KO rat model of FXS. We used the rat homolog of human isoform 17 (rat isoform X3), a highly abundant isoform.…”

Section: Introductionmentioning

confidence: 93%

Gene therapy using an ortholog of human fragile X mental retardation protein partially rescues behavioral abnormalities and EEG activity

Hooper

Wong

Niibori

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Fragile X syndrome (FXS), a neurodevelopmental disorder with no known cure, is caused by a lack of expression of the fragile X mental retardation protein (FMRP). As a singlegene disorder, FXS is an excellent candidate for viral-vectorbased gene therapy, although that is complicated by the existence of multiple isoforms of FMRP, whose individual cellular functions are unknown. We studied the effects of rat and mouse orthologs of human isoform 17, a major expressed isoform of FMRP. Injection of neonatal Fmr1 knockout rats and mice with adeno-associated viral vectors (AAV9 serotype) under the control of an MeCP2 mini-promoter resulted in widespread distribution of the FMRP transgenes throughout the telencephalon and diencephalon. Transgene expression occurred mainly in non-GABAergic neurons, with little expression in glia. Early postnatal treatment resulted in partial rescue of the Fmr1 KO rat phenotype, including improved social dominance in treated Fmr1 KO females and partial rescue of locomotor activity in males. Electro-encephalogram (EEG) recordings showed correction of abnormal slow-wave activity during the sleep-like state in male Fmr1 KO rats. These findings support the use of AAV-based gene therapy as a treatment for FXS and specifically demonstrate the potential therapeutic benefit of human FMRP isoform 17 orthologs.

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“…While our review has focussed on sex differences in sleep and circadian phenotypes in (relatively young) adult rodents, sex differences have also been shown to be modulated by aging and pathology in humans and rodents (e.g., Carrier et al, 2017 ; Kostin et al, 2020 ; Kuljis et al, 2016 ; Sun et al, 2016 ; Wong et al, 2020 ), and to emerge in pathology-associated sleep disturbances ( Gjerstad et al, 2007 ). As emphasized for the effect of targeted mutations, it is therefore tremendously important to consider sex difference in sleep/circadian functions in rodent models of pathology (or at least to investigate the two sexes).…”

Section: Discussionmentioning

confidence: 99%

“…In rats, a higher global EEG power between 0 and 100 Hz in the frontal cortex was recently reported for females (unspecified estrous cycle phase) in comparison to males during quiet wakefulness ( Wong et al, 2020 ). Of note is that this global sex difference in waking EEG activity was reversed in animals KO for Fmr1 ( Wong et al, 2020 ), a gene linked to Fragile X syndrome, morphological and neurological symptoms in humans. Concerning REMS, an absence of difference in EEG power spectrum (0.5-20 Hz) was reported between males and OVX females submitted to different gonadal hormone treatments ( Deurveilher et al, 2011 ).…”

Section: Eeg Activitymentioning

confidence: 91%

A review of the current state of knowledge on sex differences in sleep and circadian phenotypes in rodents

Dib

Gervais

Mongrain

2021

Neurobiology of Sleep and Circadian Rhythms

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Sleep is a vital part of our lives as it is required to maintain health and optimal cognition. In humans, sex differences are relatively well-established for many sleep phenotypes. However, precise differences in sleep phenotypes between male and female rodents are less documented. The main goal of this article is to review sex differences in sleep architecture and electroencephalographic (EEG) activity during wakefulness and sleep in rodents. The effects of acute sleep deprivation on sleep duration and EEG activity in male and female rodents will also be covered, in addition to sex differences in specific circadian phenotypes. When possible, the contribution of the female estrous cycle to the observed differences between males and females will be described. In general, male rodents spend more time in non-rapid eye movement sleep (NREMS) in comparison to females, while other differences between sexes in sleep phenotypes are species- and estrous cycle phase-dependent. Altogether, the review illustrates the need for a sex-based perspective in basic sleep and circadian research, including the consideration of sex chromosomes and gonadal hormones in sleep and circadian phenotypes.

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Sexually dimorphic patterns in electroencephalography power spectrum and autism-related behaviors in a rat model of fragile X syndrome

Cited by 19 publications

References 53 publications

Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome

Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome

Gene therapy using an ortholog of human fragile X mental retardation protein partially rescues behavioral abnormalities and EEG activity

A review of the current state of knowledge on sex differences in sleep and circadian phenotypes in rodents

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