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

McCullagh, Elizabeth A.; Salcedo, Ernesto E.; Huntsman, Molly M.; Klug, Achim

doi:10.1002/cne.24290

Cited by 27 publications

(32 citation statements)

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“…This increase is paralleled by a large increase in spontaneous EPSC frequency with no change in amplitude, and a similar increase in the number of synaptic endings labeled with VGLUT1 and VGLUT2 . Inhibitory synaptic transmission from MNTB to LSO is mainly unaltered . These results suggest that LSO neurons of Fmr1 knockout mice receive more synaptic inputs and input fibers from VCN, whereas the strength of each individual synapse is unaffected.…”

Section: Fmrp Regulates the Development Of Synaptic Transmission In Tmentioning

confidence: 79%

“…88 Inhibitory synaptic transmission from MNTB to LSO is mainly unaltered. 56,88 These results suggest that LSO neurons of Fmr1 knockout mice receive more synaptic inputs and input fibers from VCN, whereas the strength of each individual synapse is unaffected. One possible mechanism may be that the loss of FMRP disturbs the developmental pruning of excitatory inputs to LSO which in wild-type animals results in a sharpening of frequency tuning in these neurons.…”

Section: Synaptic Distribution Is Altered and Excitation Is Enhancementioning

confidence: 86%

“…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 . McCullagh et al showed that the number of GABAergic and glycinergic inhibitory inputs to the MNTB is decreased, as indicated by glutamate decarboxylase (GAD67) and the glycine transporter 2 (GlyT2) antibody staining .…”

Section: Fmrp Regulates the Development Of Synaptic Transmission In Tmentioning

confidence: 99%

“…55,56 McCullagh et al 56 showed that the number of GABAergic and glycinergic inhibitory inputs to the MNTB is decreased, as indicated by glutamate decarboxylase (GAD67) and the glycine transporter 2 (GlyT2) antibody staining. 56 Interestingly, these changes are specific to the tonotopic location within the nucleus, with lateral MNTB showing decreased GABAergic inhibition while medial MNTB showing decreased glycinergic inhibition. In contrast, Rotschafer et al 55 suggested strengthened inhibition by showing increased immunoreactivity for the vesicular GABA transporter (VGAT), a marker for both GABAergic and glycinergic terminal boutons.…”

Section: Synaptic Distribution Is Altered But Neurotransmission Is mentioning

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 Tmentioning

confidence: 79%

Section: Synaptic Distribution Is Altered and Excitation Is Enhancementioning

confidence: 86%

Section: Fmrp Regulates the Development Of Synaptic Transmission In Tmentioning

confidence: 99%

Section: Synaptic Distribution Is Altered But Neurotransmission Is mentioning

confidence: 99%

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Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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“…These include the anteroventral cochlear nucleus (AVCN) and the medial nucleus of the trapezoid body (MNTB), as well as the medial and lateral superior olivary nuclei to which the AVCN and MNTB project. This conclusion is supported by the finding that the auditory brainstem response (ABR) recorded in vivo is altered in adult Fmr1 Ϫ/y mice, and this may result, in part, from an alteration in the balance of excitation and inhibition (Rotschafer et al, 2015;Garcia-Pino et al, 2017;McCullagh et al, 2017).…”

Section: Introductionmentioning

confidence: 87%

Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice

El-Hassar

Song

Tan³

et al. 2019

J. Neurosci.

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Fragile X syndrome (FXS) is characterized by hypersensitivity to sensory stimuli, including environmental sounds. We compared the auditory brainstem response (ABR) recorded in vivo in mice lacking the gene (Fmr1 ؊/y ) for fragile X mental retardation protein (FMRP) with that in wild-type animals. We found that ABR wave I, which represents input from the auditory nerve, is reduced in Fmr1 ؊/y animals, but only at high sound levels. In contrast, wave IV, which represents the activity of auditory brainstem nuclei is enhanced at all sound levels, suggesting that loss of FMRP alters the central processing of auditory signals. Current-clamp recordings of neurons in the medial nucleus of the trapezoid body in the auditory brainstem revealed that, in contrast to neurons from wild-type animals, sustained depolarization triggers repetitive firing rather than a single action potential. In voltage-clamp recordings, K ϩ currents that activate at positive potentials ("high-threshold" K ϩ currents), which are required for high-frequency firing and are carried primarily by Kv3.1 channels, are elevated in Fmr1 ؊/y mice, while K ϩ currents that activate near the resting potential and inhibit repetitive firing are reduced. We therefore tested the effects of AUT2 [((4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl) benzonitrile], a compound that modulates Kv3.1 channels. AUT2 reduced the high-threshold K ϩ current and increased the low-threshold K ϩ currents in neurons from Fmr1 ؊/y animals by shifting the activation of the high-threshold current to more negative potentials. This reduced the firing rate and, in vivo, restored wave IV of the ABR. Our results from animals of both sexes suggest that the modulation of the Kv3.1 channel may have potential for the treatment of sensory hypersensitivity in patients with FXS. Key words: auditory brainstem response; AUT2; fragile X; high-and low-threshold potassium channels; medial nucleus of the trapezoid body; potassium channelsSignificance Statement mRNA encoding the Kv3.1 potassium channel was one of the first described targets of the fragile X mental retardation protein (FMRP). Fragile X syndrome is caused by loss of FMRP and, in humans and mice, causes hypersensitivity to auditory stimuli. We found that components of the auditory brain response (ABR) corresponding to auditory brainstem activity are enhanced in mice lacking FMRP. This is accompanied by hyperexcitability and altered potassium currents in auditory brainstem neurons. Treatment with a drug that alters the voltage dependence of Kv3.1 channels normalizes the imbalance of potassium currents, as well as ABR responses in vivo, suggesting that such compounds may be effective in treating some symptoms of fragile X syndrome.

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Structural arrangement of auditory brainstem nuclei in the bats Phyllostomus discolor and Carollia perspicillata

Pätz

Console-Meyer

Felmy

2022

J of Comparative Neurology

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The structure of the mammalian auditory brainstem is evolutionarily highly plastic, and distinct nuclei arrange in a species-dependent manner. Such anatomical variability is present in the superior olivary complex (SOC) and the nuclei of the lateral lemniscus (LL). Due to the structure-function relationship in the auditory brainstem, the identification of individual nuclei supports the understanding of sound processing. Here, we comparatively describe the nucleus arrangement and the expression of functional markers in the auditory brainstem of the two bat species Phyllostomus discolor and Carollia perspicillata. Using immunofluorescent labeling, we describe the arrangement and identity of the SOC and LL nuclei based on the expression of synaptic markers (vesicular glutamate transporter 1 and glycine transporter 2), calcium-binding proteins, as well as the voltage-gated ion channel subunits Kv1.1 and HCN1. The distribution of excitatory and inhibitory synaptic labeling appears similar between both species and matches with that of other mammals. The detection of calcium-binding proteins indicates species-dependent differences and deviations from other mammals. Kv1.1 and HCN1 show largely the same expression pattern in both species, which diverges from other mammals, indicating functional adaptations in the cellular physiology of bat neurons.

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

Cited by 27 publications

References 88 publications

Mechanisms underlying auditory processing deficits in Fragile X syndrome

Mechanisms underlying auditory processing deficits in Fragile X syndrome

Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice

Structural arrangement of auditory brainstem nuclei in the bats Phyllostomus discolor and Carollia perspicillata

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