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mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

Neuropsychopharmacology volume 48, pages 877–886 (2023)Cite this article

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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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Fig. 1: CDKL5 loss is responsible for both the disruption of mGluR5-Homer1bc interaction and the reduction of mGluR5 localization in the cortical neuropil.
Fig. 2: CDKL5 loss tampers with both mEPSCs and NMDA current.
Fig. 3: Acute CDPPB treatment rescues visual response, sensorimotor and memory deficits in Cdkl5-/y mice.
Fig. 4: Structural defects exhibited by Cdkl5-/y mice cortices are rescued by an acute CDPPB injection.
Fig. 5: Aberrant expression of excitatory synaptic proteins in the BA17 cortex of CDD patients.

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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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Authors and Affiliations

  1. “Rita Levi-Montalcini” Department of Neuroscience, University of Turin, Turin, Italy

    Antonia Gurgone, Riccardo Pizzo, Alessandra Raspanti, Giuseppe Chiantia, Sunaina Devi, Debora Comai, Noemi Morello, Federica Pilotto, Sara Gnavi & Maurizio Giustetto

  2. BIO@SNS lab, Scuola Normale Superiore, 56124, Pisa, Italy

    Leonardo Lupori & Tommaso Pizzorusso

  3. Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, 56128, Pisa, Italy

    Raffaele Mazziotti

  4. NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50135, Florence, Italy

    Giulia Sagona

  5. Institute of Neuroscience, CNR, 56124, Pisa, Italy

    Elena Putignano & Tommaso Pizzorusso

  6. NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019, Sesto Fiorentino, Florence, Italy

    Alessio Nocentini & Claudiu T. Supuran

  7. Department of Drug Science, University of Turin, Turin, Italy

    Andrea Marcantoni

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  1. Antonia Gurgone
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  18. Maurizio Giustetto
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Contributions

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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Correspondence to Maurizio Giustetto.

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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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