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

Molecular Psychiatry (2025)Cite this article

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Abstract

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 may be a therapeutic strategy to correct sensory processing deficits in FXS.

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Fig. 1: Antagonism of CB1Rs and DAGLα rescues prolonged Up states in Fmr1 KO cortical slices.
Fig. 2: Genetic reduction of Cnr1 in GABAergic neurons, but not glutamatergic neurons, rescues prolonged Up states in the Fmr1 KO.
Fig. 3: Genetic reduction of Cnr1 in GABAergic neurons or rimonabant treatment rescue the decreased synchronization of chirp-driven cortical activity in the Fmr1 KO.
Fig. 4: Both genetic reduction of Cnr1 in GABAergic neurons and rimonabant rescue decreased synchronization of pulse-driven cortical activity at 80 Hz in the Fmr1 KO.
Fig. 5: Both genetic reduction of Cnr1 in GABAergic neurons and rimonabant rescue decreased synchronization of pulse-driven cortical activity at 40 Hz in the Fmr1 KO.
Fig. 6: Distinct effects of genetic and pharmacological reduction of CB1R activity on resting state EEG.

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Data availability

The authors declare that all data supporting the findings of this study are available in the main text or the supplementary materials. Datasets are available from the corresponding authors upon request. Correspondence and requests for materials should be addressed to KMH and DKB (Kimberly.Huber@UTSouthwestern.edu and devin.binder@ucr.edu). Labview software for analysis of Up states is available at https://github.com/jaygibson244/GibsonHuber-UP-states.git. The MATLAB code used to perform statistical analysis for chirp, 40 and 80 Hz ASSR is available at Github: https://github.com/CarrieRJonak/MEA-EEG_ITPC.

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Acknowledgements

We would like to acknowledge Jacob E. Bowles and Christopher Williams for technical assistance with genotyping and Dr. Laurent Gautron for assistance with RNAscope. This work was supported by NIH grants U54HD082008 and U54HD104461 (KMH, JRG, DKB) and P30DK127984 (UTSW Metabolic Core).

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  1. These authors contributed equally: D. Gonzalez, CR Jonak.

Authors and Affiliations

  1. Department of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA

    D. Gonzalez, M. Bernabucci, G. Molinaro, K. Collins, JR Gibson & KM Huber

  2. Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA, USA

    CR Jonak, SA Assad & DK Binder

  3. Neuroscience Graduate Program, University of California, Riverside, CA, USA

    DK Binder

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Contributions

DG, CRJ, MB, GM, KC, and SAA performed experiments and data analysis. JRG developed software for data acquisition and analysis and performed data analysis. JRG, DKB, and KMH contributed to experimental design, data analysis, wrote the manuscript and obtained funding for the project.

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Correspondence to DK Binder or KM Huber.

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All experimental procedures have been approved by the Institutional Animal Care and Use Committees at UT Southwestern (Protocol #’s 2015-101252; 2017-101986) or UC Riverside (Protocol #: #20190015) and conducted in full accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Gonzalez, D., Jonak, C., Bernabucci, M. et al. Enhanced CB1 receptor function in GABAergic neurons mediates hyperexcitability and impaired sensory-driven synchrony of cortical circuits in Fragile X Syndrome model mice. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03366-6

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