Binder, D. | Search bioRxiv

bioRxiv2025

Enhanced CB1 receptor function in GABAergic neurons mediates hyperexcitability and impaired sensory-driven synchrony of cortical circuits in Fragile X Syndrome model mice

Electroencephalographic (EEG) recordings in individuals with Fragile X Syndrome (FXS) and the mouse model of FXS (Fmr1 KO) display cortical hyperexcitability at rest, as well as deficits in sensory-driven cortical network synchrony. A form of circuit hyperexcitability is observed in ex vivo cortical slices of Fmr1 KO mice as prolonged persistent activity, or Up, states. It is unknown if the circuit mechanisms that cause prolonged Up states contribute to FXS-relevant EEG phenotypes. Here we examined the role of endocannabinoids (eCB) in prolonged Up states in slices and resting and sensory-driven EEG phenotypes in awake Fmr1 KO mice. Bidirectional changes in eCB function are reported in the Fmr1 KO that depend on synapse type (excitatory or inhibitory). We demonstrate that pharmacological or genetic reduction of Cannabinoid Receptor 1 (CB1R) in GABAergic neurons rescues prolonged cortical Up states and deficits in sensory-driven cortical synchrony in Fmr1 KO mice. In support of these findings, recordings from Fmr1 KO cortical Layer (L) 2/3 pyramidal neurons revealed enhanced CB1R-mediated suppression of inhibitory synaptic currents. In contrast, genetic reduction of Cnr1 in glutamatergic neurons did not affect Up state duration, but deletion of Fmr1 in the same neurons was sufficient to cause long Up states. These findings support a model where loss of Fmr1 in glutamatergic neurons leads to enhanced CB1R-mediated suppression of GABAergic synaptic transmission, prolonged cortical circuit activation and reduced sensory-driven circuit synchronization. Results suggest that antagonism of CB1Rs as a therapeutic strategy to correct sensory processing deficits in FXS.

neuroscience↗

bioRxiv2024

Frontal Cortex Hyperactivation and Gamma Desynchrony in Fragile X Syndrome: Correlates of Auditory Hypersensitivity

Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in top-down modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.

neuroscience↗