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Targeted therapy of cognitive deficits in fragile X syndrome

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cris.lastimport.scopus2024-02-12T20:33:30Z
dc.abstract.enBreaking an impasse in finding mechanism-based therapies of neuropsychiatric disorders requires a strategic shift towards alleviating individual symptoms. Here we present a symptom and circuit-specific approach to rescue deficits of reward learning in Fmr1 knockout mice, a model of Fragile X syndrome (FXS), the most common monogenetic cause of inherited mental disability and autism. We use high-throughput, ecologically-relevant automated tests of cognition and social behavior to assess effectiveness of the circuit-targeted injections of designer nanoparticles, loaded with TIMP metalloproteinase inhibitor 1 protein (TIMP-1). Further, to investigate the impact of our therapeutic strategy on neuronal plasticity we perform long-term potentiation recordings and high-resolution electron microscopy. We show that central amygdala-targeted delivery of TIMP-1 designer nanoparticles reverses impaired cognition in Fmr1 knockouts, while having no impact on deficits of social behavior, hence corroborating symptom-specificity of the proposed approach. Moreover, we elucidate the neural correlates of the highly specific behavioral rescue by showing that the applied therapeutic intervention restores functional synaptic plasticity and ultrastructure of neurons in the central amygdala. Thus, we present a targeted, symptom-specific and mechanism-based strategy to remedy cognitive deficits in Fragile X syndrome.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorKNAPSKA, EWELINA
dc.contributor.authorKACZMAREK, LESZEK
dc.contributor.authorMEYZA, KSENIA
dc.contributor.authorChaturvedi, Mayank
dc.contributor.authorGÓRKIEWICZ, TOMASZ
dc.contributor.authorŁĘSKI, SZYMON
dc.contributor.authorPuścian, Alicja
dc.contributor.authorDziembowska, Magdalena
dc.contributor.authorNikolaev, T.
dc.contributor.authorChmielewska, J. J.
dc.contributor.authorWołyniak, M.
dc.contributor.authorNowicka, K.
dc.contributor.authorBorowska, J.
dc.contributor.authorWiniarski, M.
dc.date.accessioned2024-01-26T09:41:24Z
dc.date.available2024-01-26T09:41:24Z
dc.date.issued2022
dc.description.financePublikacja bezkosztowa
dc.description.number6
dc.description.volume27
dc.identifier.doi10.1038/S41380-022-01527-5
dc.identifier.issn1359-4184
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/121552
dc.identifier.weblinkhttps://www.nature.com/articles/s41380-022-01527-5.pdf
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofMolecular Psychiatry
dc.relation.pages2766-2776
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.titleTargeted therapy of cognitive deficits in fragile X syndrome
dc.typeJournalArticle
dspace.entity.typePublication