Oxytocin receptor agonist improves social deficits by regulating hippocampal neural plasticity in Shank3 knockout mice

ABSTRACT: Autism spectrum disorder is a prevalent neurodevelopmental disorder lacking effective pharmacological agents targeting core socialbehavioral symptoms. Oxytocin receptor represents a promising therapeutic target, yet the clinical benefits of exogenous oxytocin remain limited and inconsistent. This study used Shank3 knockout mice as a model of autism spectrum disorder to evaluate the efficacy of Lit001, a selective oxytocin receptor agonist, in ameliorating social deficits and to investigate its underlying mechanisms. Wild-type (normal) and homozygous Shank3 knockout mice were assigned to six experimental groups treated with single-dose or repeated Lit001 administration, with an additional oxytocin receptor antagonist co-administration group included for pharmacological reversal validation. We found that Lit001 exerted neuroprotective effects in the hippocampus, attenuated pathological microglial activation, increased hippocampal acetylcholine receptor and dopamine receptor D2 expression, restored dendritic spine and nerve fiber integrity, and reversed transcriptional abnormalities associated with synaptic transmission and energy metabolism. Pretreatment with an oxytocin receptor antagonist abolished these therapeutic effects. Social motivation improved rapidly after short-term treatment but diminished within one month, whereas social novelty preference exhibited a delayed yet sustained improvement. Transcriptomic analysis further demonstrated that oxytocin receptor blockade reversed Lit001-induced transcriptional remodeling. Patch-clamp recordings confirmed that Lit001 increased the frequency of spontaneous excitatory postsynaptic currents. Distinct from exogenous oxytocin, Lit001 selectively activates oxytocin receptors without altering peripheral oxytocin levels. The selective oxytocin receptor agonist Lit001 ameliorates core social deficits in Shank3 knockout mice, potentially through oxytocin receptor-dependent neural regeneration and remodeling of hippocampal neural plasticity.