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

التفاصيل البيبلوغرافية
العنوان:	SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome.
المؤلفون:	Stamenkovic V; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA., Lautz JD; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA., Harsh FM; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA., Smith SEP; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. seps@uw.edu.; Department of Pediatrics, University of Washington, Seattle, WA, USA. seps@uw.edu.; Graduate Program in Neuroscience, University of Washington, Seattle, WA, USA. seps@uw.edu.
المصدر:	Molecular psychiatry [Mol Psychiatry] 2024 May; Vol. 29 (5), pp. 1392-1405. Date of Electronic Publication: 2024 Jan 31.
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Nature Publishing Group Specialist Journals Country of Publication: England NLM ID: 9607835 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5578 (Electronic) Linking ISSN: 13594184 NLM ISO Abbreviation: Mol Psychiatry Subsets: MEDLINE
أسماء مطبوعة:	Publication: 2000- : Houndmills, Basingstoke, UK : Nature Publishing Group Specialist Journals Original Publication: Houndmills, Hampshire, UK ; New York, NY : Stockton Press, c1996-
مواضيع طبية MeSH:	Fragile X Syndrome/metabolism , Fragile X Syndrome/drug therapy , Fragile X Mental Retardation Protein/metabolism , Fragile X Mental Retardation Protein/genetics , Disease Models, Animal* , src-Family Kinases/metabolism , Benzodioxoles/pharmacology , Proto-Oncogene Proteins c-fyn/metabolism , Neurons/metabolism , Neurons*/drug effects, Animals ; Mice ; Male ; Receptors, Metabotropic Glutamate/metabolism ; Signal Transduction/drug effects ; Phenotype ; Synapses/metabolism ; Synapses/drug effects ; Protein Interaction Maps/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Cerebral Cortex/metabolism ; Cerebral Cortex/drug effects ; Quinazolines
مستخلص:	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. (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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المشرفين على المادة:	139135-51-6 (Fragile X Mental Retardation Protein) 0 (Fmr1 protein, mouse) EC 2.7.10.2 (src-Family Kinases) 9KD24QGH76 (saracatinib) 0 (Benzodioxoles) EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn) 0 (Receptors, Metabotropic Glutamate) EC 2.7.10.2 (Fyn protein, mouse) 0 (Receptors, N-Methyl-D-Aspartate) 0 (Quinazolines)
تواريخ الأحداث:	Date Created: 20240131 Date Completed: 20240620 Latest Revision: 20240620
رمز التحديث:	20240621
DOI:	10.1038/s41380-024-02418-7
PMID:	38297084
قاعدة البيانات:	MEDLINE

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تدمد:	1476-5578
DOI:	10.1038/s41380-024-02418-7