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other·preclinical research, biomedical research, neurology, pediatrics·PMC10156697

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

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 18 authors, 7 centres

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TL;DR

Acute and subchronic treatment with mGluR5 positive allosteric modulators (PAMs) rescued synaptic, cortical, and behavioral deficits in the mice without causing seizures.

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The study used a CDKL5 knockout (Cdkl5-/-y) mouse model and two post-mortem CDD patient brains to explore mGluR5 dysfunction. Researchers found reduced synaptic expression and interaction of mGluR5 with Homer1bc in both mice and human tissue, alongside altered basal and NMDA-mediated synaptic transmission in cortical neurons. Acute and 5-day treatment with mGluR5 PAMs (CDPPB and RO68) rescued molecular (increased Homer1bc and mGluR5 synaptic expression), physiological (restored mGluR5-mediated potentiation of NMDA currents), and functional (improved cortical visual evoked potentials and behavioral deficits) endophenotypes. The study demonstrates that mGluR5 signaling is impaired but not abolished in CDD and suggests mGluR5 PAMs as a promising therapeutic target.

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other

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preclinical research

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ORIGINAL PAPER

PMC10156697

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

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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ABSTRACT

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. Keywords: neurodevelopmental disorders, synapses, NMDA-mediated current, synaptic transmission, cerebral cortex

CITATION EXPORT

Antonia Gurgone, Riccardo Pizzo, Alessandra Raspanti et al.. mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. (2022). https://doi.org/10.1038/s41386-022-01412-3

AUTHORS

18 · 7 CENTRES

Antonia Gurgone, Riccardo Pizzo, Alessandra Raspanti, Giuseppe Chiantia, Sunaina Devi, Debora Comai, Noemi Morello, Federica Pilotto, Sara Gnavi, Leonardo Lupori, Raffaele Mazziotti, Giulia Sagona, Elena Putignano, Alessio Nocentini, Claudiu T Supuran, Andrea Marcantoni, Tommaso Pizzorusso, Maurizio Giustetto

1"Rita Levi-Montalcini" Department of Neuroscience, University of Turin, Turin (Italy)
2BIO@SNS lab, Scuola Normale Superiore, 56124 Pisa, Italy
3Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy
4NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50135 Florence, Italy
5Institute of Neuroscience, CNR, 56124 Pisa, Italy
5NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019 Sesto Fiorentino (Florence), Italy
6Department of Drug Science, University of Turin, Turin, Italy