mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder
Antonia Gurgone1, Riccardo Pizzo1, Alessandra Raspanti1
1"Rita Levi-Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.
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.
Insights
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental disease. Targeting metabotropic glutamate receptor 5 (mGluR5) with specific drugs corrected synaptic and behavioral deficits in mouse models of CDD.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe neurodevelopmental condition with no cure, stemming from mutations in the CDKL5 gene.
- CDD presents with early seizures, intellectual disability, autistic traits, and sensory impairments, highlighting the urgent need for therapeutic targets.
- Class I metabotropic glutamate receptors 5 (mGluR5) are implicated in synaptic functions disrupted by CDKL5 deficiency.
Purpose of the Study:
- To investigate the role of mGluR5 in CDKL5 deficiency disorder (CDD) pathophysiology.
- To determine if modulating mGluR5 activity can ameliorate CDD-related defects.
Main Methods:
- Studied the interaction between Homer1bc and mGluR5 in CDKL5-deficient mice.
- Assessed synaptic localization and function of mGluR5 in the absence of CDKL5.
- Administered mGluR5 positive-allosteric modulators (PAMs) like CDPPB and RO6807794 to CDKL5-deficient mice.
- Examined synaptic organization in the visual cortex of CDD patients.
Main Results:
- CDKL5 loss impairs Homer1bc-mGluR5 complex binding, mGluR5 synaptic localization, and mGluR5-mediated neuronal responses.
- Administration of mGluR5 PAMs (CDPPB, RO6807794) rescued synaptic, functional, and behavioral deficits in Cdkl5-/y mice.
- CDD patient visual cortex showed synaptic changes mirroring those in mutant mice, including reduced mGluR5 expression.
Conclusions:
- mGluR5 signaling is critically affected in CDKL5 deficiency disorder.
- Pharmacological stimulation of mGluR5 with PAMs offers a potential therapeutic strategy for CDD.
- mGluR5 represents a promising druggable target for treating CDD and its associated neurological impairments.
