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

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 ß-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.

Balance Between Projecting Neuronal Populations of the Nucleus Accumbens Controls Social Behavior in Mice.

BACKGROUND: Deficient social interactions are a hallmark of major neuropsychiatric disorders, and accumulating evidence points to altered social reward and motivation as key underlying mechanisms of these pathologies. In the present study, we further explored the role of the balance of activity between D1 and D2 receptor-expressing striatal projection neurons (D1R- and D2R-SPNs) in the control of social behavior, challenging the hypothesis that excessive D2R-SPN activity, rather than deficient D1R-SPN activity, compromises social behavior. METHODS: We selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor-mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function, and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the nucleus accumbens (NAc) and pharmacological compounds repressing D2R-SPN. RESULTS: Targeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated motor skill learning, and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum. Ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior but impaired motor skill learning and decreased anxiety levels. Deletion of D2R-SPNs in the NAc produced motor stereotypies but facilitated social behavior and impaired motor skill learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and observed a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition. CONCLUSIONS: Repressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficits in neuropsychiatric disorders.

Cocaine represses protein phosphatase-1Cß through DNA methylation and Methyl-CpG Binding Protein-2 recruitment in adult rat brain.

Repeated cocaine exposure induces epigenetic factors such as DNA methyl-binding proteins, indicating that resulting changes in gene expression are mediated by alterations in brain DNA methylation. While the activity of protein phosphatase type-1 (PP1) is involved in cocaine effects and in brain plasticity, the expression of the PP1Cß catalytic subunit gene was identified here as modulated by cocaine. Its expression was induced together with that of PP1Cγ in the brain of Methyl-CpG Binding Protein-2 (Mecp2) mutant mice, whereas PP1Cα expression was not affected, illustrating a different regulation of PP1C isoforms. Repeated cocaine administration was found to increase DNA methylation at the PP1Cß gene together with its binding to Mecp2 in rat caudate putamen, establishing a link between two genes involved in cocaine-related effects and in learning and memory processes. Cocaine also increased DNMT3 expression, resulting in PP1Cß repression that did not occur in the presence of DNMT inhibitor. Cocaine-induced PP1Cß repression was observed in several brain structures, as evaluated by RT-qPCR, immunohistochemistry and Western blot, but did not occur after a single cocaine injection. Our data demonstrate that PP1Cß is a direct MeCP2-target gene in vivo. They suggest that its repression may participate to behavioral adaptations triggered by the drug.