Abnormal neuronal morphology and neurochemistry in the auditory brainstem of Fmr1 knockout rats

Ruby, Kristen N; Falvey, K.; Kulesza, Randy J.

doi:10.1016/j.neuroscience.2015.06.061

Cited by 35 publications

(48 citation statements)

References 88 publications

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“…This orientation of neurons is lost in both ASD and FXS patients, implicating disrupted dendritic branching in MSO. Although only one human FXS subject has been examined so far, very similar cellular changes have been detected in the MSO of a Fmr1 knockout rat strain (; Figure C,D), strongly supporting the notion that these MSO changes are common phenotypes in FXS.…”

Section: Fmrp Regulates the Development Of Synaptic Transmission In Tsupporting

confidence: 65%

“…Strong FMRP expression is detected in the VCN‐MSO circuit across taxa, including gerbils, rats, and humans Figure B). Similarly, almost all neurons of NM and NL in alligator and chicken brainstems contain exceptionally high levels of FMRP .…”

Section: Fmrp Regulates the Development Of Synaptic Transmission In Tmentioning

confidence: 99%

“…Immunocytochemical studies of various cellular and synaptic markers have suggested that excitatory and inhibitory inputs to MNTB may be altered, but the direction of this alteration is not yet clear. A study using Fmr1 knockout rats revealed that the MNTB contains significantly fewer terminals immunoreactive for calretinin, a marker for calyx terminals from VCN . Two studies have reported presynaptic alterations in inhibitory inputs to MNTB in Fmr1 knockout mice .…”

Section: Fmrp Regulates the Development Of Synaptic Transmission In Tmentioning

confidence: 99%

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Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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Autism spectrum disorders (ASD) are strongly associated with auditory hypersensitivity or hyperacusis (difficulty tolerating sounds). Fragile X syndrome (FXS), the most common monogenetic cause of ASD, has emerged as a powerful gateway for exploring underlying mechanisms of hyperacusis and auditory dysfunction in ASD. This review discusses examples of disruption of the auditory pathways in FXS at molecular, synaptic, and circuit levels in animal models as well as in FXS individuals. These examples highlight the involvement of multiple mechanisms, from aberrant synaptic development and ion channel deregulation of auditory brainstem circuits, to impaired neuronal plasticity and network hyperexcitability in the auditory cortex. Though a relatively new area of research, recent discoveries have increased interest in auditory dysfunction and mechanisms underlying hyperacusis in this disorder. This rapidly growing body of data has yielded novel research directions addressing critical questions regarding the timing and possible outcomes of human therapies for auditory dysfunction in ASD.

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Section: Fmrp Regulates the Development Of Synaptic Transmission In Tsupporting

confidence: 65%

Section: Fmrp Regulates the Development Of Synaptic Transmission In Tmentioning

confidence: 99%

Section: Fmrp Regulates the Development Of Synaptic Transmission In Tmentioning

confidence: 99%

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Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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“…Many non-cortical brain regions are involved in auditory processing, auditory induced seizure behavior, and have been shown to be altered in the Fmr1 KO mice. Altered spontaneous UP states may not be a critical determinant in AGS susceptibility in these mice, but may contribute to other aberrant behavior in KO mice [92–94]. It is also possible that systemic administration of acamprosate may not have a similar effect on UP state duration as observed in slice application of the drug.…”

Section: Discussionmentioning

confidence: 99%

Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety

Schaefer

Davenport

Grainger

et al. 2017

J Neurodevelop Disord

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BackgroundFragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene (FMR1) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of acamprosate and the significance of the molecule’s calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of acamprosate were assessed in the Fmr1 -/y (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments.Methods Fmr1 KO mice and their wild-type (WT) littermates were utilized to assess acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic acamprosate treatment and any potential effects of the calcium moiety using CaCl2 treatment on behavior and nuclear ERK1/2 activation.ResultsAcamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation.ConclusionsThese data indicate that acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of acamprosate in these instances.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-017-9184-y) contains supplementary material, which is available to authorized users.

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“…Several anatomical studies of autistic individuals have shown alterations in the size and orientation of brainstem nuclei, specifically a reduction in cell number within MNTB, MSO, and LSO (Kulesza & Mangunay, ; Kulesza, Lukose, & Stevens, ). In an FXS knockout rat model, many brainstem neurons had smaller soma and in the superior paraolivary nucleus (SPN) there was reduced expression of glutamic acid decarboxylase (GAD67) (Ruby, Falvey, & Kulesza, ). In the same study, the authors showed a reduction in number of calretinin positive terminals, which is a marker for calyx axons and terminals in the MNTB (Ruby et al, ).…”

Section: Introductionmentioning

confidence: 99%

Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of Fragile X syndrome

McCullagh

Salcedo

Huntsman

et al. 2017

J of Comparative Neurology

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Hyperexcitability and the imbalance of excitation/inhibition are one of the leading causes of abnormal sensory processing in Fragile X syndrome (FXS). The precise timing and distribution of excitation and inhibition is crucial for auditory processing at the level of the auditory brainstem, which is responsible for sound localization ability. Sound localization is one of the sensory abilities disrupted by loss of the Fragile X Mental Retardation 1 (Fmr1) gene. Using triple immunofluorescence staining we tested whether there were alterations in the number and size of presynaptic structures for the three primary neurotransmitters (glutamate, glycine and GABA) in the auditory brainstem of Fmr1 knockout mice. We found decreases in either glycinergic or GABAergic inhibition to the medial nucleus of the trapezoid body (MNTB) specific to the tonotopic location within the nucleus. MNTB is one of the primary inhibitory nuclei in the auditory brainstem and participates in the sound localization process with fast and well-timed inhibition. Thus, a decrease in inhibitory afferents to MNTB neurons should lead to greater inhibitory output to the projections from this nucleus. In contrast, we did not see any other significant alterations in balance of excitation/inhibition in any of the other auditory brainstem nuclei measured, suggesting that the alterations observed in the MNTB are both nucleus and frequency specific. We furthermore show that glycinergic inhibition may be an important contributor to imbalances in excitation and inhibition in FXS and that the auditory brainstem is a useful circuit for testing these imbalances.

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Abnormal neuronal morphology and neurochemistry in the auditory brainstem of Fmr1 knockout rats

Cited by 35 publications

References 88 publications

Mechanisms underlying auditory processing deficits in Fragile X syndrome

Mechanisms underlying auditory processing deficits in Fragile X syndrome

Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety

Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of Fragile X syndrome

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