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bioRxiv · 10.1101/2023.06.20.545800

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

Stamenkovic, V.·Lautz, J. D.·Harsh, F. M.·Smith, S. E. P.
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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 investigated how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN. In cultured cortical neurons or acute cortical slices from P7, P17 and P60 FMR1-/y mice, the unstimulated protein interaction networks state resembled that of wildtype littermates stimulated with neurotransmitter agonists, demonstrating resting state pre-activation of signaling networks. We identified the Src family kinase (SFK) Fyn as a network hub, because many interactions involving Fyn were pre-activated. We tested whether targeting Fyn in FMR1-/y mice could modify disease phenotypes, and found that Saracatinib (AZD-0530), 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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Stamenkovic, V., Lautz, J. D., Harsh, F. M., Smith, S. E. P.. 2023-06-23. SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome. https://doi.org/10.1101/2023.06.20.545800

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