Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 May 1:248:109889.
doi: 10.1016/j.neuropharm.2024.109889. Epub 2024 Feb 22.

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder

Mathieu Fonteneau  1 , Agathe Brugoux  2 , Déborah Jaccaz  3 , John E Donello  4 , Pradeep Banerjee  5 , Julie Le Merrer  2 , Jérôme Aj Becker  2
Affiliations
Free article

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder

Mathieu Fonteneau et al. Neuropharmacology. .
Free article

Abstract

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by deficient social communication and interaction together with restricted, stereotyped behaviors. Currently approved treatments relieve comorbidities rather than core symptoms. Since excitation/inhibition balance and synaptic plasticity are disrupted in ASD, molecules targeting excitatory synaptic transmission appear as highly promising candidates to treat this pathology. Among glutamatergic receptors, the NMDA receptor has received particular attention through the last decade to develop novel allosteric modulators. Here, we show that positive NMDA receptor modulation by zelquistinel, a spirocyclic β-lactam platform chemical, relieves core symptoms in two genetic and one environmental mouse models of ASD. A single oral dose of zelquistinel rescued, in a dose-response manner, social deficits and stereotypic behavior in Shank3Δex13-16-/- mice while chronic intraperitoneal administration promoted a long-lasting relief of such autistic-like features in these mice. Subchronic oral mid-dose zelquistinel treatment demonstrated durable effects in Shank3Δex13-16-/-, Fmr1-/- and in utero valproate-exposed mice. Carry-over effects were best maintained in the Fmr1 null mouse model, with social parameters being still fully recovered two weeks after treatment withdrawal. Among recently developed NMDA receptor subunit modulators, zelquistinel displays a promising therapeutic potential to relieve core symptoms in ASD patients, with oral bioavailability and long-lasting effects boding well for clinical applications. Efficacy in three mouse models with different etiologies supports high translational value. Further, this compound represents an innovative pharmacological tool to investigate plasticity mechanisms underlying behavioral deficits in animal models of ASD.

Keywords: Autism spectrum disorder; Genetic mouse models; N-Methyl-d-Aspartate receptor; Social behavior; Stereotypies; Valproic acid.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest This work was supported by Allergan Laboratories, Gate Neurosciences, the Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Tours. Allergan Laboratories and Gate Neurosciences provided fundings and had a role in the study design. Other institutions had a role in funding salaries for permanent staff and providing optimal technical and scientific environment for research. Pradeep Banerjee is an employee of Allergan (now part of AbbVie). John E. Donello was an employee of Allergan and is now an advisor of Gate Neurosciences. All the other authors declare that they have no conflict of interest.

Substances