Genetic background mutations drive neural circuit hyperconnectivity in a fragile X syndrome model

Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by silence of the fmr1 gene and the deficiency of Fragile X mental retardation protein (FMRP). Patients present neuronal alterations that lead to severe intellectual disability and altered sleep rhythms. However, the neural circuit mechanisms underlying FXS remain unclear. Previous studies have suggested that metabolic glutamate and gamma-aminobutyric acid (GABA) receptors/circuits are two counter-balanced factors involved in FXS pathophysiology. More and more studies demonstrated that attenuated GABAergic circuits in the absence of FMRP are critical for abnormal progression of FXS. Here, we reviewed the changes of GABA neural circuits that were attributed to intellectual-deficient FXS, from several aspects including deregulated GABA metabolism, decreased expressions of GABA receptor subunits, and impaired GABAergic neural circuits. Furthermore, the activities of GABA neural circuits are modulated by circadian rhythm of FMRP metabolism and reviewed the abnormal condition of FXS mice or patients.

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Auditory Brainstem Responses in the C57BL/6J Fragile X Syndrome Knockout Mouse Model

10.1101/2021.10.27.466191 ◽

2021 ◽

Author(s):

Amita Chawla ◽

Elizabeth A McCullagh

Keyword(s):

Fragile X Syndrome ◽

Genetic Background ◽

Fragile X ◽

Auditory Brainstem ◽

Human Condition ◽

Auditory Brainstem Responses ◽

Common Symptom ◽

Knockout Mouse Model ◽

Brainstem Response ◽

Hearing Range

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X Syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brainstem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure hearing range, monaural and binaural auditory responses in hemizygous males, homozygous females and heterozygous females compared to wildtype mice. Consistent with previous work we showed no difference in morphological parameters across genotypes or sexes. Male FXS mice had increased threshold for high frequency hearing at 64 kHz compared to wildtype males, while females had no difference in hearing range between genotypes. In contrast, female homozygous FXS mice had decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Lastly, FXS males had increased latency of the binaural interaction component (BIC) at 0 ITD compared to wildtype males. These findings further clarify auditory brainstem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

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