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bioRxiv · 10.1101/2024.10.15.617900

Disrupted Hippocampal-Prefrontal Networks In A Rat Model Of Fragile X Syndrome: A Study Linking Neural Dynamics To Autism-Like Behavioral Impairments

Ouardouz, M.·Khalife, M.·Jasinski, P.·Mahoney, J. M.·Hernan, A.·Scott, R.
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Abstract

Fragile X Syndrome (FXS) is associated with autism spectrum disorder (ASD) symptoms that are associated with cognitive, learning, and behavioral challenges. We investigated how known molecular disruptions in the Fmr1 knockout (FMR-KO) rat model of FXS negatively impact hippocampal-prefrontal cortex (H-PFC) neural network activity and consequent behavior. MethodsFMR-KO and control rats underwent a battery of behavioral tests assessing sociability, memory, and anxiety. Single-unit electrophysiology recordings were then conducted to measure patterns of neural activity in H-PFC circuit. Advanced mathematical models were used to characterize the patterns that were then compared between groups using generalized linear mixed models. ResultsFMR-KO rats demonstrated significant behavioral deficits in sociability, spatial learning, and anxiety, aligning with symptoms of ASD. At the neural level, these rats exhibited abnormal firing patterns in the H-PFC circuit that is critical for learning, memory, and social behavior. The neural networks in FMR-KO rats were also less densely connected and more fragmented, particularly in hippocampal-PFC correlated firing. These findings suggest that disruptions in neural network dynamics underlie the observed behavioral impairments in FMR-KO rats. ConclusionFMR-KO significantly disrupts several characteristics of action potential firing in the H-PFC network, leading to deficits in social behavior, memory, and anxiety, as seen in FXS. This disruption is characterized by less organized and less resilient hippocampal-PFC networks. These findings suggest that therapeutic strategies aimed at normalizing neural dynamics, such as with brain stimulation, could potentially improve behavior and cognitive functions in autistic individuals. HIGHLIGHTSO_LIFragile X Syndrome is associated with autism, cognitive challenges and anxiety C_LIO_LIThe loss of Fmr1 protein disrupts processes involved in building neural networks C_LIO_LIThe consequence is abnormal neural dynamics in hippocampal-prefrontal cortex networks C_LIO_LINormalization of dynamics could improve outcomes in FXS and ASD C_LI

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Ouardouz, M., Khalife, M., Jasinski, P., Mahoney, J. M., Hernan, A., Scott, R.. 2024-10-16. Disrupted Hippocampal-Prefrontal Networks In A Rat Model Of Fragile X Syndrome: A Study Linking Neural Dynamics To Autism-Like Behavioral Impairments. https://doi.org/10.1101/2024.10.15.617900

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