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[Preprint]. 2024 Oct 16:2024.10.15.617900. [Version 1] doi: 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

Mohamed Ouardouz, Patrick Jasinski, Mohamed Khalife, J Matthew Mahoney, Amanda E Hernan, Rod C Scott
PMCID: PMC11507762  PMID: 39464036

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.

Methods

FMR-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.

Results

FMR-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.

Conclusion

FMR-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.

HIGHLIGHTS

  • Fragile X Syndrome is associated with autism, cognitive challenges and anxiety

  • The loss of Fmr1 protein disrupts processes involved in building neural networks

  • The consequence is abnormal neural dynamics in hippocampal-prefrontal cortex networks

  • Normalization of dynamics could improve outcomes in FXS and ASD

Full Text Availability

The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server.


Articles from bioRxiv are provided here courtesy of Cold Spring Harbor Laboratory Preprints

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