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bioRxiv · 10.1101/2025.10.13.682100

Early developmental characterization of gap-induced prepulse inhibition and habituation in the Fragile X Syndrome mouse model

Abdullah, A.·Liu, X.·Murari, K.·Yan, J.·Cheng, N.
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Abstract

IntroductionAtypical sensory processing, particularly auditory hypersensitivity, is a common and debilitating phenotype of Fragile X Syndrome (FXS). Electrophysiology studies in FMR1-knockout (KO) mice previously observed hyperexcitability at the auditory cortex (AC), with enhanced neuronal firing to auditory stimuli. Prepulse inhibition (PPI), a behavioral measure of sensorimotor gating, is robustly impaired in FXS individuals. Interestingly, a related paradigm called gap-induced inhibition of the acoustic startle (GPIAS) is mediated by the AC, and a previous study observed decreased GPIAS in mature FMR1-KO mice. Further, habituation is also an important sensory filtering mechanism, which has been reported to be impaired in mature FMR1-KO mice. However, not much is known about GPIAS and habituation in FMR1- KO mice during early development. MethodsWe evaluated GPIAS in male and female FMR1-KO mice at post-natal days 15 (P15), 20 (P20) and 30 (P30). The paradigm consisted of a prepulse stimulus (a gap in a continuous background noise) followed by a startle stimulus, with an inter-stimulus interval of 50 or 100 ms. Habituation was assessed prior to the GPIAS trials, with a series of startle only stimulus. ResultsWe observed a trend for genotype difference in acoustic startle response (ASR) magnitude, particularly in the female mice at P30. No significant genotype differences were noted in GPIAS or latency of ASR. Response duration was significantly increased in the male FMR1-KO mice compared to their WT counterparts during early development. Significant genotype differences were also observed in habituation and sensitization. In terms of development, we observed a significant increase in GPIAS with maturation. Furthermore, we also observed significant changes in the magnitude, response latency and duration of ASR with maturation. Finally, significant sex differences were observed in ASR magnitude and duration. ConclusionOur findings suggest that behavioral responses to auditory stimuli are dynamic during development and differ between females and males, an important consideration for future study design. Additionally, the FMR1-KO mice display habituation deficits during early development, which could be an ideal window for addressing auditory hypersensitivity in FXS.

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Abdullah, A., Liu, X., Murari, K., Yan, J., Cheng, N.. 2025-10-14. Early developmental characterization of gap-induced prepulse inhibition and habituation in the Fragile X Syndrome mouse model. https://doi.org/10.1101/2025.10.13.682100

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