Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei of<i>Fmr1</i>Knockout Mice

Rotschafer, Sarah E.; Cramer, Karina S.

doi:10.1523/eneuro.0264-17.2017

Cited by 30 publications

(47 citation statements)

References 79 publications

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“…(Borst & Soria van Hoeve, 2012;Forsythe, 1994;Held, 1893;Tolbert & Morest, 1982). It was previously shown that VGLUT2 immunoreactivity in MNTB did not change between ages P6 and P14 in FVB mice (Rotschafer & Cramer, 2017). We found no age-related to our previous findings (Milinkeviciute et al, 2019).…”

Section: Discussionsupporting

confidence: 48%

CX3CR1 mutation alters synaptic and astrocytic protein expression, topographic gradients, and response latencies in the auditory brainstem

Milinkeviciute

Chokr

Castro

et al. 2021

J of Comparative Neurology

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The precise and specialized circuitry in the auditory brainstem develops through adaptations of cellular and molecular signaling. We previously showed that elimination of microglia during development impairs synaptic pruning that leads to maturation of the calyx of Held, a large encapsulating synapse that terminates on neurons of the medial nucleus of the trapezoid body (MNTB). Microglia depletion also led to a decrease in glial fibrillary acidic protein (GFAP), a marker for mature astrocytes. Here, we investigated the role of signaling through the fractalkine receptor (CX3CR1), which is expressed by microglia and mediates communication with neurons. CX3CR1 −/− and wild-type mice were studied before and after hearing onset and at 9 weeks of age. Levels of GFAP were significantly increased in the MNTB in mutants at 9 weeks. Pruning was unaffected at the calyx of Held, but we found an increase in expression of glycinergic synaptic marker in mutant mice at P14, suggesting an effect on maturation of inhibitory inputs. We observed disrupted tonotopic gradients of neuron and calyx size in MNTB in mutant mice.Auditory brainstem recording (ABR) revealed that CX3CR1 −/− mice had normal thresholds and amplitudes but decreased latencies and interpeak latencies, particularly for the highest frequencies. These results demonstrate that disruption of fractalkine signaling has a significant effect on auditory brainstem development.Our findings highlight the importance of neuron-microglia-astrocyte communication in pruning of inhibitory synapses and establishment of tonotopic gradients early in postnatal development.

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Section: Discussionsupporting

confidence: 48%

CX3CR1 mutation alters synaptic and astrocytic protein expression, topographic gradients, and response latencies in the auditory brainstem

Milinkeviciute

Chokr

Castro

et al. 2021

J of Comparative Neurology

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“…Several recent studies described anatomic alterations in the sound localization pathway of Fmr1 mice, which lead to altered physiologic properties Strumbos et al, 2010;Rotschafer et al, 2015;Garcia-Pino et al, 2017;McCullagh et al, 2017;Rotschafer and Cramer, 2017;Curry et al, 2018;El-Hassar et al, 2019;Lu, 2019). These alterations include differences in synaptic strength and connectivity; differences in postsynaptic ion channels, postsynaptic input resistance, and altered firing properties; alterations in action potential shape; and differences in macroscopic physiologic properties such as ABRs.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Auditory and Binaural Spatial Hearing in a Fragile X Syndrome Mouse Model

McCullagh

Poleg

Greene

et al. 2020

eNeuro

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The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location and determine spatial acuity. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in fragile X syndrome (FXS), it is not known whether these changes cause spatial acuity deficits in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with variations in sound (gap, location, masking) as the prepulse stimulus, was used on Fmr1 knock-out mice and B6 controls. Specifically, Fmr1 mice show decreased PPI compared with wild-type mice during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared with wild-type mice. Last, Fmr1 mice have increased latency to respond in these tasks, suggesting additional impairments in the pathway responsible for reacting to a startling sound. This study further supports data in humans with FXS that show similar deficits in PPI.

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“…Furthermore, it has been shown that Fmr1 −/y mouse strain exhibits sensorial impairments, in addition to behavioral and cognitive alterations similar to those observed in FXS patients (Bakker et al, 1994; Nimchinsky et al, 2001; Yan et al, 2004; Dolen et al, 2007; Spencer et al, 2011; Hebert et al, 2014; Ghilan et al, 2018), concomitantly displaying auditory, olfactory and tactile disorders (Larson et al, 2008; Arnett et al, 2014; Rotschafer and Cramer, 2017). However, to our knowledge, the visual skills of Fmr1 −/y mice have not been investigated using specific visual tests yet.…”

Section: Introductionmentioning

confidence: 92%

Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

Felgerolle

Hébert

Ardourel

et al. 2019

Front. Behav. Neurosci.

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Fragile X Syndrome (FXS), the most common inherited form of human intellectual disability (ID) associated with autistic-like behaviors, is characterized by dys-sensitivity to sensory stimuli, especially vision. In the absence of Fragile Mental Retardation Protein (FMRP), both retinal and cerebral structures of the visual pathway are impaired, suggesting that perception and integration of visual stimuli are altered. However, behavioral consequences of these defects remain unknown. In this study, we used male Fmr1−/y mice to further define visual disturbances from a behavioral perspective by focusing on three traits characterizing visual modality: perception of depth, contrasts and movements. We performed specific tests (Optomotor Drum, Visual Cliff) to evaluate these visual modalities, their evolution from youth to adulthood, and to assess their involvement in a cognitive task. We show that Fmr1−/y mice exhibit alteration in their visual skills, displaying impaired perspective perception, a drop in their ability to understand a moving contrasted pattern, and a defect in contrasts discrimination. Interestingly, Fmr1−/y phenotypes remain stable over time from adolescence to late adulthood. Besides, we report that color and shape are meaningful for the achievement of a cognitive test involving object recognition. Altogether, these results underline the significance of visual behavior alterations in FXS conditions and relevance of assessing visual skills in neuropsychiatric models before performing behavioral tasks, such as cognitive assessments, that involve visual discrimination.

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Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei ofFmr1Knockout Mice

Cited by 30 publications

References 79 publications

CX3CR1 mutation alters synaptic and astrocytic protein expression, topographic gradients, and response latencies in the auditory brainstem

CX3CR1 mutation alters synaptic and astrocytic protein expression, topographic gradients, and response latencies in the auditory brainstem

Characterization of Auditory and Binaural Spatial Hearing in a Fragile X Syndrome Mouse Model

Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

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