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SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome

Molecular Psychiatry (2024)Cite this article

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Abstract

Glutamatergic synapses encode information from extracellular inputs using dynamic protein interaction networks (PINs) that undergo widespread reorganization following synaptic activity, allowing cells to distinguish between signaling inputs and generate coordinated cellular responses. Here, we investigate how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN downstream of NMDA receptor or metabotropic glutamate receptor (mGluR) stimulation. In cultured cortical neurons or acute cortical slices from P7, P17 and P60 FMR1−/y mice, the unstimulated protein interaction network state resembled that of wildtype littermates stimulated with mGluR agonists, demonstrating resting state pre-activation of mGluR signaling networks. In contrast, interactions downstream of NMDAR stimulation were similar to WT. We identified the Src family kinase (SFK) Fyn as a network hub, because many interactions involving Fyn were pre-activated in FMR1−/y animals. We tested whether targeting SFKs in FMR1−/y mice could modify disease phenotypes, and found that Saracatinib (SCB), an SFK inhibitor, normalized elevated basal protein synthesis, novel object recognition memory and social behavior in FMR1−/y mice. However, SCB treatment did not normalize the PIN to a wild-type-like state in vitro or in vivo, but rather induced extensive changes to protein complexes containing Shank3, NMDARs and Fyn. We conclude that targeting abnormal nodes of a PIN can identify potential disease-modifying drugs, but behavioral rescue does not correlate with PIN normalization.

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Fig. 1: FMR1−/y cultured cortical neurons show tonic activation of DHPG-responsive protein interactions.
Fig. 2: Hyperactive tonic DHPG-like signaling throughout development in FMR1−/y brain slices.
Fig. 3: Pharmacological reduction of SFK activity restores protein synthesis rates in FMR1−/y acute cortical slices.
Fig. 4: SCB treatment rescues impaired social approach and object recognition memory in FMR1−/y mice.
Fig. 5: Acute SCB does not normalize protein interaction networks.
Fig. 6: SCB does not normalize protein interaction networks in vivo.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

This work was supported by NIH grants MH113545 and MH121487 (to SEPS), a fellowship from the FRAXA research foundation (to VS), and a NARSAD grant from the Brain and Behavior Research Foundation (to SEPS). The authors thank all members of the SEPS laboratory, as well as Drs. B.K. Reed and M. Chau for providing insight and thoughtful discussions.

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Authors and Affiliations

  1. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA

    Vera Stamenkovic, Jonathan D. Lautz, Felicia M. Harsh & Stephen E. P. Smith

  2. Department of Pediatrics, University of Washington, Seattle, WA, USA

    Stephen E. P. Smith

  3. Graduate Program in Neuroscience, University of Washington, Seattle, WA, USA

    Stephen E. P. Smith

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  1. Vera Stamenkovic
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Conceptualization: SEPS and JDL. Investigation: VS, JDL, FH. Data analysis: VS, JDL, SEPS. Writing: VS and SEPS. Funding acquisition and supervision: VS and SEPS.

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Correspondence to Stephen E. P. Smith.

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Seattle Children’s Research Institute has filed a preliminary patent application describing the use of SCB in Fragile X. The authors declare no other competing interests.

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Stamenkovic, V., Lautz, J.D., Harsh, F.M. et al. SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02418-7

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