Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

Saré, Rachel Michelle; Figueroa, Christopher; Lemons, Abigail; Loutaev, Inna; Smith, Carolyn Beebe

doi:10.3390/brainsci9010013

Cited by 14 publications

(8 citation statements)

References 30 publications

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“…Conversely, both juvenile and adult Fmr1-Δ exon 8 rats showed an increased number of total entries in the arms of the elevated plus maze when compared to WT controls, thus confirming the hyperlocomotion displayed by Fmr1-Δ exon 8 rats across development. In line with these results, the extensively characterized Fmr1-KO mouse model of FXS has been shown to display motor alterations and hyperactivity [63][64][65][66][67] , although normal locomotor activity has also been also reported in rat models of FXS 68,69 . Conversely, we found that Fmr1-Δ exon 8 rats did not show stereotypic/repetitive behaviors in the hole-board test, as the number of head dippings did not differ from their WT controls.…”

Section: Discussionsupporting

confidence: 54%

FMR1 deletion in rats induces hyperactivity with no changes in striatal dopamine transporter availability

D’Elia

Schiavi

Manduca

et al. 2022

Sci Rep

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Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder emerging in early life characterized by impairments in social interaction, poor verbal and non-verbal communication, and repetitive patterns of behaviors. Among the best-known genetic risk factors for ASD, there are mutations causing the loss of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) leading to Fragile X syndrome (FXS), a common form of inherited intellectual disability and the leading monogenic cause of ASD. Being a pivotal regulator of motor activity, motivation, attention, and reward processing, dopaminergic neurotransmission has a key role in several neuropsychiatric disorders, including ASD. Fmr1Δexon 8 rats have been validated as a genetic model of ASD based on FMR1 deletion, and they are also a rat model of FXS. Here, we performed behavioral, biochemical and in vivo SPECT neuroimaging experiments to investigate whether Fmr1Δexon 8 rats display ASD-like repetitive behaviors associated with changes in striatal dopamine transporter (DAT) availability assessed through in vivo SPECT neuroimaging. At the behavioral level, Fmr1Δexon 8 rats displayed hyperactivity in the open field test in the absence of repetitive behaviors in the hole board test. However, these behavioral alterations were not associated with changes in striatal DAT availability as assessed by non-invasive in vivo SPECT and Western blot analyses.

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Section: Discussionsupporting

confidence: 54%

FMR1 deletion in rats induces hyperactivity with no changes in striatal dopamine transporter availability

D’Elia

Schiavi

Manduca

et al. 2022

Sci Rep

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“…In particular, we observe a significant increase in marbles buried in the marble burying test and an increase in nesting behavior in the fragile X animals. Our marble burying data are consistent with the current understanding that increased burrowing behavior in this assay is indicative of increased anxiety-like behaviors in Fmr1 −/− mice [76][77][78]. Our nest-building data indicate that FXS animals engage in more nest-building behavior than wild type, contrary to previously reported data [79][80][81].…”

Section: Discussionsupporting

confidence: 89%

A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice

et al. 2021

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Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS.

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“…Beyond repeat expansions in the FMR1 gene, a number of rare pathogenic point mutations have been reported that cause developmental delay and ID reminiscent of FXS [153][154][155][156][157]. Further evidence suggests that mutations in the autosomal homolog FXR2 gene might also contribute to ID [158][159][160]. Whilst variants affecting the related FXR1 gene confer risk to schizophrenia, bipolar disorder, and autism [161][162][163][164][165], the genetic link between FMR1 and psychiatric disorders derives from enrichment of association within the gene targets of FMRP (among which the fragile-X family genes themselves are included).…”

Section: Fmrp and Fmrp Targets In Psychiatric Genomic Studiesmentioning

confidence: 99%

FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

et al. 2020

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There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (FMR1) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (CYFIP1) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of FMR1 and CYFIP1 to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.

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Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

Cited by 14 publications

References 30 publications

FMR1 deletion in rats induces hyperactivity with no changes in striatal dopamine transporter availability

FMR1 deletion in rats induces hyperactivity with no changes in striatal dopamine transporter availability

A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice

FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

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