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other·neurology, pediatrics, neuroscience, developmental neurobiology, pharmacology·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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POPULATIONCdkl5-/y mice (CDKL5 deficiency disorder model) and primary cortical neuron cultures from these mice; also postmortem BA17 cortex from 2 CDD patients and 2 neurotypical controls

INTERVENTIONAcute or sub-chronic (5-day) intraperitoneal administration of mGluR5 positive allosteric modulators (PAMs): CDPPB (3 mg/kg) or RO6807794 (0.3 mg/kg)

COMPARISONVehicle-treated Cdkl5-/y mice and Cdkl5+/y wild-type littermates; DHPG (mGluR5 agonist) vs CDPPB in electrophysiology experiments

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TL;DR

This study demonstrates that the metabotropic glutamate receptor mGluR5 is abnormally expressed and functional in the cerebral cortex of Cdkl5-/y mice, a model of CDKL5 deficiency disorder (CDD). Acute or sub-chronic treatment with mGluR5 positive allosteric modulators (PAMs) such as CDPPB rescued synaptic, electrophysiological, visual, sensorimotor, and memory deficits in mutant mice. These findings identify mGluR5 as a promising therapeutic target for CDD, with translational support from postmortem human CDD brain tissue showing similar synaptic protein reductions.

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**Background:** CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental condition caused by mutations in the CDKL5 gene, encoding a serine/threonine kinase highly expressed in forebrain during synaptogenesis. CDKL5 phosphorylates multiple substrates involved in cytoskeletal function, dendritic spine maturation, and excitatory synaptic transmission. Previous work showed that Cdkl5-/y mice exhibit cortical abnormalities including reduced postsynaptic scaffolding proteins PSD-95 and Homer1bc, disrupted AKT-mTOR signaling, impaired excitatory transmission, and behavioral deficits modeling human CDD. Given that mGluR5 (metabotropic glutamate receptor 5) requires interaction with Homer1bc for proper signaling and is involved in synaptogenesis and plasticity, the authors hypothesized that mGluR5 dysfunction contributes to CDD pathology and that positive allosteric modulation of mGluR5 could be therapeutic.

**Methods:** Experiments used Cdkl5-/y mice and wild-type Cdkl5+/y littermates. Co-immunoprecipitation (co-IP) of cortical synaptosomal fractions assessed mGluR5-Homer1bc binding. Immunofluorescence quantified puncta density for mGluR5, Homer1bc, PSD-95, ARC, and c-Fos in S1 and V1 cortices. Whole-cell patch-clamp recordings in primary S1 cortical neuron cultures measured miniature EPSCs and NMDA-evoked currents (INMDA) before and after application of the mGluR5 agonist DHPG (100 μM) or the mGluR5 PAM CDPPB (10 μM). In vivo, mice received acute (single i.p.) or sub-chronic (5 consecutive days) injections of CDPPB (3 mg/kg) or RO6807794 (0.3 mg/kg). Visual cortical responses were measured by transcranial intrinsic optical signal (IOS) imaging. Behavioral tests included adhesive tape-removal (sensorimotor), Y-maze spontaneous alternations (working memory), open-field (locomotion), and hind-limb clasping scoring. Postmortem BA17 cortex from 2 CDD patients (5.7 and 30 years old) and 2 age/sex-matched controls was analyzed by immunofluorescence and western blotting for PSD-95, Homer1bc, VGluT1, and mGluR5.

**Key Results:** Co-IP revealed significantly reduced mGluR5-Homer1bc binding in Cdkl5-/y cortex (p < 0.05) despite unchanged total protein levels. mGluR5+ puncta density was strongly reduced in layers II-III and V of S1 cortex in mutants (p < 0.05). In cultured neurons, mEPSC inter-event interval was increased in Cdkl5-/y neurons (p < 0.05) while amplitude was unchanged. DHPG application increased mEPSC IEI in wild-type but not mutant neurons. NMDA-evoked currents were significantly reduced in Cdkl5-/y neurons (p < 0.01). DHPG potentiated INMDA in 73% of wild-type neurons but only 29% of mutant neurons (p < 0.05). Critically, CDPPB potentiated INMDA in 83% of Cdkl5-/y neurons (vs 29% with DHPG, p < 0.0001), restoring mGluR5-NMDA coupling. Acute CDPPB treatment in vivo rescued visual cortex responses (IOS amplitude: vehicle-Cdkl5-/y vs CDPPB-Cdkl5-/y post-injection p < 0.05; CDPPB-Cdkl5-/y reached wild-type levels, p = 0.6). Sensorimotor deficits in tape-removal were normalized (vehicle-Cdkl5+/y vs CDPPB-Cdkl5-/y p > 0.4). Y-maze working memory was rescued (vehicle-Cdkl5+/y vs CDPPB-Cdkl5-/y p > 0.4). Locomotor hyperactivity was not affected by CDPPB. CDPPB restored Homer1bc+ and mGluR5+ puncta density in S1 and V1 cortices of mutants (p < 0.01 to p < 0.001) and normalized ARC+ cell density in V1 (p < 0.001). Similar rescue of Homer1bc+ puncta and c-Fos+ cell density was achieved with RO6807794 (p < 0.05 to p < 0.001). Sub-chronic (5-day) CDPPB treatment rescued Homer1bc+ puncta density (p < 0.01), hind-limb clasping (p < 0.01), tape-removal latency (p > 0.7 vs wild-type), visual responses (p < 0.01), and c-Fos/ARC expression (p < 0.01). In human BA17 cortex, CDD cases showed reduced PSD-95+, Homer1bc+, and VGluT1+ puncta density and reduced protein expression of PSD-95, Homer1bc, and mGluR5 by western blot compared to controls.

**Clinical Implications:** This study identifies mGluR5 as a novel therapeutic target for CDD, demonstrating that positive allosteric modulation can rescue synaptic, functional, and behavioral deficits in a mouse model. The finding that mGluR5 PAMs restore NMDA receptor function, postsynaptic protein organization, cortical activation, and multiple behavioral phenotypes—without inducing seizures—supports their potential clinical utility. The demonstration that human CDD postmortem cortex recapitulates the same synaptic protein reductions (mGluR5, Homer1bc, PSD-95) strengthens translational relevance. Cortical visual impairment, a clinically measurable biomarker in CDD patients, was rescued by CDPPB, suggesting it could serve as a translational endpoint. The study adds CDD to the growing list of neurodevelopmental disorders (Fragile X, Phelan-McDermid, TSC, Rett syndrome) in which mGluR5 signaling is a convergent pathogenic pathway. Limitations include the small human sample (n=2), the need for long-term safety and efficacy studies, and the incomplete understanding of the molecular mechanism by which CDPPB restores mGluR5 function in the absence of CDKL5.

PICO

PPOPULATION

Cdkl5-/y mice (CDKL5 deficiency disorder model) and primary cortical neuron cultures from these mice; also postmortem BA17 cortex from 2 CDD patients and 2 neurotypical controls

IINTERVENTION

Acute or sub-chronic (5-day) intraperitoneal administration of mGluR5 positive allosteric modulators (PAMs): CDPPB (3 mg/kg) or RO6807794 (0.3 mg/kg)

OOUTCOME

mGluR5-Homer1bc binding (co-IP), mGluR5+ puncta density (immunofluorescence), miniature EPSC parameters, NMDA current amplitude, visual cortex response (intrinsic optical signal imaging), adhesive tape-removal test latency, Y-maze spontaneous alternations, open-field locomotion, Homer1bc+ and ARC+ puncta density, c-Fos+ cell density, hind-limb clasping

STUDY TYPE

other

SPECIALTY

neurology

SUMMARISED BY

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FIDELITY CHECK

100% · A

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