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Anandamide and 2-arachidonoylglycerol differentially modulate autistic-like traits in a genetic model of autism based on FMR1 deletion in rats

Neuropsychopharmacology volume 48, pages 897–907 (2023)Cite this article

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Abstract

Autism spectrum disorder (ASD) has a multifactorial etiology. Major efforts are underway to understand the neurobiological bases of ASD and to develop efficacious treatment strategies. Recently, the use of cannabinoid compounds in children with neurodevelopmental disorders including ASD has received increasing attention. Beyond anecdotal reports of efficacy, however, there is limited current evidence supporting such an intervention and the clinical studies currently available have intrinsic limitations that make the interpretation of the findings challenging. Furthermore, as the mechanisms underlying the beneficial effects of cannabinoid compounds in neurodevelopmental disorders are still largely unknown, the use of drugs targeting the endocannabinoid system remains controversial. Here, we studied the role of endocannabinoid neurotransmission in the autistic-like traits displayed by the recently validated Fmr1-Δexon 8 rat model of autism. Fmr1-Δexon 8 rats showed reduced anandamide levels in the hippocampus and increased 2-arachidonoylglycerol (2-AG) content in the amygdala. Systemic and intra-hippocampal potentiation of anandamide tone through administration of the anandamide hydrolysis inhibitor URB597 ameliorated the cognitive deficits displayed by Fmr1-Δexon 8 rats along development, as assessed through the novel object and social discrimination tasks. Moreover, blockade of amygdalar 2-AG signaling through intra-amygdala administration of the CB1 receptor antagonist SR141716A prevented the altered sociability displayed by Fmr1-Δexon 8 rats. These findings demonstrate that anandamide and 2-AG differentially modulate specific autistic-like traits in Fmr1-Δexon 8 rats in a brain region-specific manner, suggesting that fine changes in endocannabinoid mechanisms contribute to ASD-related behavioral phenotypes.

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Fig. 1: AEA and 2-AG levels were altered in a region-specific manner in the brain of Fmr1-Δexon 8 rats.
Fig. 2: qPCR analysis of the main components of the ECS in the hippocampus of juvenile Fmr1-Δexon 8 rats.
Fig. 3: qPCR analysis of the main components of the ECS in the amygdala of juvenile Fmr1-Δexon 8 rats.
Fig. 4: Potentiation of AEA tone through systemic administration of URB597 rescued the impaired object and social discrimination abilities of Fmr1-Δexon 8 rats.
Fig. 5: Intra-hippocampal potentiation of AEA tone rescued the impaired object and social discrimination abilities of Fmr1-Δexon 8 rats, while blockade of CB1 cannabinoid receptors in the amygdala restored their altered sociability.

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Funding

This work was supported by Autism Speaks grant #11690 (AM and VT), MIUR PRIN 2017 grant # SXEXT5 (VT), Regione Lazio “Gruppi di ricerca 2020” grant # PROT. A0375-2020-36550 (VT) and operating funds from the Canadian Institutes of Health Research (MNH).

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Author notes

  1. These authors contributed equally: Sara Schiavi, Antonia Manduca.

Authors and Affiliations

  1. Department of Science, Roma Tre University, Rome, Italy

    Sara Schiavi, Antonia Manduca, Emilia Carbone, Valeria Buzzelli, Alessandro Rava, Alessandro Feo, Fabrizio Ascone & Viviana Trezza

  2. Neuroendocrinology, Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Rome, Italy

    Antonia Manduca

  3. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

    Maria Morena & Patrizia Campolongo

  4. Neuropsychopharmacology Unit, IRCSS Fondazione Santa Lucia, Rome, Italy

    Maria Morena & Patrizia Campolongo

  5. Departments of Cell Biology and Anatomy & Psychiatry, Hotchkiss Brain Institute and Mathison Center for Mental Health Research and Education, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Maria Morena & Matthew N. Hill

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  1. Sara Schiavi
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  2. Antonia Manduca
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  11. Viviana Trezza
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Contributions

SS and AM performed, analyzed, and contributed to the design of the behavioral experiments. MM and MNH performed and analyzed the biochemical experiments to measure endocannabinoid levels. EC, AR, AF, and FA performed the qPCR and Western blotting experiments. EC, VB, and PC contributed to the behavioral experiments. SS, AM, and VT wrote the paper. VT supervised the project, designed the experiments, and wrote, revised, and edited the paper. All authors contributed to the paper and approved the submitted version.

Corresponding author

Correspondence to Viviana Trezza.

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Schiavi, S., Manduca, A., Carbone, E. et al. Anandamide and 2-arachidonoylglycerol differentially modulate autistic-like traits in a genetic model of autism based on FMR1 deletion in rats. Neuropsychopharmacol. 48, 897–907 (2023). https://doi.org/10.1038/s41386-022-01454-7

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