Behavioral and Synaptic Circuit Features in a Zebrafish Model of Fragile X Syndrome

The majority of the human genome is comprised of non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs) such as fragile X syndrome (FXS). After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed byDicerendoribonuclases to form microRNA (miRNA)-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs) is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced DNA methylation of theFMR15′-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptionalFMR1gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, whileFMR1inactivation augments metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD), leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.

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Altered brain-wide auditory networks in a zebrafish model of fragile X syndrome

BMC Biology ◽

10.1186/s12915-020-00857-6 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 7

Author(s):

Lena Constantin ◽

Rebecca E. Poulsen ◽

Leandro A. Scholz ◽

Itia A. Favre-Bulle ◽

Michael A. Taylor ◽

...

Keyword(s):

Fragile X Syndrome ◽

Visual Motion ◽

Fragile X ◽

Auditory Pathway ◽

Brain Regions ◽

Torus Semicircularis ◽

Auditory Stimuli ◽

Auditory Information ◽

Zebrafish Model ◽

Cellular Resolution

Abstract Background Loss or disrupted expression of the FMR1 gene causes fragile X syndrome (FXS), the most common monogenetic form of autism in humans. Although disruptions in sensory processing are core traits of FXS and autism, the neural underpinnings of these phenotypes are poorly understood. Using calcium imaging to record from the entire brain at cellular resolution, we investigated neuronal responses to visual and auditory stimuli in larval zebrafish, using fmr1 mutants to model FXS. The purpose of this study was to model the alterations of sensory networks, brain-wide and at cellular resolution, that underlie the sensory aspects of FXS and autism. Results Combining functional analyses with the neurons’ anatomical positions, we found that fmr1−/− animals have normal responses to visual motion. However, there were several alterations in the auditory processing of fmr1−/− animals. Auditory responses were more plentiful in hindbrain structures and in the thalamus. The thalamus, torus semicircularis, and tegmentum had clusters of neurons that responded more strongly to auditory stimuli in fmr1−/− animals. Functional connectivity networks showed more inter-regional connectivity at lower sound intensities (a − 3 to − 6 dB shift) in fmr1−/− larvae compared to wild type. Finally, the decoding capacities of specific components of the ascending auditory pathway were altered: the octavolateralis nucleus within the hindbrain had significantly stronger decoding of auditory amplitude while the telencephalon had weaker decoding in fmr1−/− mutants. Conclusions We demonstrated that fmr1−/− larvae are hypersensitive to sound, with a 3–6 dB shift in sensitivity, and identified four sub-cortical brain regions with more plentiful responses and/or greater response strengths to auditory stimuli. We also constructed an experimentally supported model of how auditory information may be processed brain-wide in fmr1−/− larvae. Our model suggests that the early ascending auditory pathway transmits more auditory information, with less filtering and modulation, in this model of FXS.

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