Abstract
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology. To this aim, we studied Class I metabotropic glutamate receptors 5 (mGluR5) because of their important role in the neuropathological signs produced by the lack of CDKL5 in-vivo, such as defective synaptogenesis, dendritic spines formation/maturation, synaptic transmission and plasticity. Importantly, mGluR5 function strictly depends on the correct expression of the postsynaptic protein Homer1bc that we previously found atypical in the cerebral cortex of Cdkl5−/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the binding strength of Homer1bc-mGluR5 complexes, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators (PAMs), i.e., 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioral defects shown by Cdkl5−/y mice. Notably, in the visual cortex of 2 CDD patients we found changes in synaptic organization that recapitulate those of mutant CDKL5 mice, including the reduced expression of mGluR5, suggesting that these receptors represent a promising therapeutic target for CDD.
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Funding
This work was supported by research grants from: University of Pennsylvania Orphan Disease Center on behalf of LouLou Foundation (CDKL5 PILOT GRANT PROGRAM n. CDKL5 - 17 - 106 – 01) and from Associazione CDKL5 Insieme verso la cura (Italy) to MG and TP; The International Foundation for CDKL5 Research, Associazione Albero di Greta and Fondazione CRT (n. 2018.0889) and by Fondazione Telethon-Italy (Grants nn. GGP15098 and GGP19045) to MG.
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AG and MG conceived and designed the study. AG performed biochemical experiments. LL, GS, RM, and EP performed IOS experiments. SG performed experiments on human tissues, AG, RP, NM, and FP performed behavioural experiments, AG, RP, SD and DC performed immunofluorescence experiments. AM and GC performed electrophysiological experiments. CS, AN synthesized and provided RO6807794; AG, RP, AR, SD, TP, AM, and MG analyzed the data. AG and MG wrote the manuscript.
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The study was conducted in accordance with European Community Council Directive 2010/63/UE for care and use of experimental animals with protocols approved by the Italian Minister for Scientific Research (Authorization number 38/2020-PR) and the Bioethics Committee of the University of Torino, Italy.
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Gurgone, A., Pizzo, R., Raspanti, A. et al. mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder. Neuropsychopharmacol. 48, 877–886 (2023). https://doi.org/10.1038/s41386-022-01412-3
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DOI: https://doi.org/10.1038/s41386-022-01412-3