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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We are thankful to Thomas G. Custer and Katie Ferguson for the critical reading of the manuscript and to Svitlana Antoniuk for the invaluable technical support.
This work was supported by a grant from Switzerland through the Swiss Contribution to the enlarged European Union (PSPB-210/2010), European Research Council Starting Grant (H 415148), grants from the National Science Center (2013/08/W/NZ4/00691 and 2015/18/E/NZ4/00600), the Foundation for Polish Science (MAB/2018/10): The Nencki-European Molecular Biology Laboratory Center of Excellence for Neural Plasticity and Brain Disorders BRAINCITY project, carried out within the International Research Agendas program of the Foundation for Polish Science, supported by the European Union under the European Regional Development Fund, and a Foundation for Polish Science (FNP) Team grant (Team/2016-1/6 to KN and LK). MC was supported by “Mobilność Plus”, a fellowship from Polish Ministry of Science and Higher Education grant number 1291/MOB/IV/2015/0. JJC was supported by the National Science Center grant 2017/27/N/NZ1/01381.
The authors declare no competing interests.
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Puścian, A., Winiarski, M., Borowska, J. et al. Targeted therapy of cognitive deficits in fragile X syndrome. Mol Psychiatry 27, 2766–2776 (2022). https://doi.org/10.1038/s41380-022-01527-5