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Purinergic Signalling Mediates Aberrant Excitability of Developing Neuronal Circuits in the Fmr1 Knockout Mouse Model

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Abstract

Neuronal hyperexcitability within developing cortical circuits is a common characteristic of several heritable neurodevelopmental disorders, including Fragile X Syndrome (FXS), intellectual disability and autism spectrum disorders (ASD). While this aberrant circuitry is typically studied from a neuron-centric perspective, glial cells secrete soluble factors that regulate both neurite extension and synaptogenesis during development. The nucleotide-mediated purinergic signalling system is particularly instrumental in facilitating these effects. We recently reported that within a FXS animal model, the Fmr1 KO mouse, the purinergic signalling system is upregulated in cortical astrocytes leading to altered secretion of synaptogenic and plasticity-related proteins. In this study, we examined whether elevated astrocyte purinergic signalling also impacts neuronal morphology and connectivity of Fmr1 KO cortical neurons. Here, we found that conditioned media from primary Fmr1 KO astrocytes was sufficient to enhance neurite extension and complexity of both wildtype and Fmr1 KO neurons to a similar degree as UTP-mediated outgrowth. Significantly enhanced firing was also observed in Fmr1 KO neuron-astrocyte co-cultures grown on microelectrode arrays but was associated with large deficits in firing synchrony. The selective P2Y2 purinergic receptor antagonist AR-C 118925XX effectively normalized much of the aberrant Fmr1 KO activity, designating P2Y2 as a potential therapeutic target in FXS. These results not only demonstrate the importance of astrocyte soluble factors in the development of neural circuitry, but also show that P2Y purinergic receptors play a distinct role in pathological FXS neuronal activity.

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Acknowledgements

We thank Dr. Laurie Doering for his valuable technical support and the Scottish Rite Charitable Foundation of Canada for funding this work.

Funding

This work was supported by a grant from the Scottish Rite Charitable Foundation of Canada (#21107) that supports mental health research.

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Authors and Affiliations

  1. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

    Kathryn E. Reynolds, Eileen Huang, Monica Sabbineni, Eliza Wiseman, Matt Napier & Angela L. Scott

  2. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada

    Nadeem Murtaza

  3. Department of Psychology, Neuroscience, and Behaviour, McMaster University, Hamilton, ON, Canada

    Desmond Ahuja & Kathryn M. Murphy

  4. University Health Network, Toronto, ON, Canada

    Karun K. Singh

  5. Department of Molecular and Cellular Biology, University of Guelph, 488 Gordon St, Guelph, ON, Canada

    Matt Napier & Angela L. Scott

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Kathryn Reynolds and Angela Scott wrote the main manuscript. Kathryn Reynolds prepared all figures. Kathryn Reynolds, Eileen Huang, Monica Sabbineni, Eliza Wiseman, Nadeem Murtaza, Matt Napier, Karun Singh, and Angela Scott were involved in data collection and experimental design contributing to Figs. 1, 2, 3, 4 and 5. Desmond Ahuja and Kathryn Murphy analyzed data and helped prepare Fig. 6. Angela Scott prepared Fig. 7. All authors reviewed the manuscript. Angela Scott received the grant for funding the project.

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Reynolds, K.E., Huang, E., Sabbineni, M. et al. Purinergic Signalling Mediates Aberrant Excitability of Developing Neuronal Circuits in the Fmr1 Knockout Mouse Model. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04181-w

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