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Puścian, A; Winiarski, M; Borowska, J; Łęski, S; Górkiewicz, T; Chaturvedi, M; Nowicka, K; Wołyniak, M; Chmielewska, J J; Nikolaev, T; Meyza, K; Dziembowska, M; Kaczmarek, L; Knapska, E
Molecular psychiatry, 06/2022, Letnik: 27, Številka: 6Journal Article
Breaking 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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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