The therapeutic potential of psychedelics on the behavioral and synaptic abnormalities of the Shank3 mouse model of Autism Spectrum Disorder

Introduction: Autistic Spectrum Disorder (ASD) is a heterogeneous set of neurodevelopmental disorders defined by distinctive behavioral core symptoms, such as reduced sociability and stereotypy, and impaired communication skills. Haploinsufficiency of the SH3 and multiple ankyrin repeat domains (Shank) 3 gene is associated with Phelan-McDermid Syndrome, a rare genetic ASD, and idiopathic ASD forms as well. Shank3 is a multi-domain protein playing a crucial scaffolding role at the excitatory postsynaptic site. Shank3 KO mice exhibit social deficit and obsessive self-injurious grooming, associated with cortico-striatal synaptic defects. Evidence from this and other ASD models points to the synapse as a key element in ASD pathophysiology, therefore functional synaptic rescue could represent an effective therapeutic strategy. In this respect, a group of chemically heterogeneous compounds sharing psychedelic activity exhibit strong dendritogenic and synaptogenic activity in vitro and in vivo.

Methods: With behavioral test, slice electrophysiology and single neuron morphometric analysis, we extended the characterization of the neurological phenotype of Shank3B +/- mice and tested the post-acute effects of a sub-anasthetic/halluginogenic single dose of ketamine and N, N-dimethyltryptamine.

Results: In Shank3B +/- mice, social deficit was reverted 24 hours after a single, subanaesthetic dose (10 mg/kg) of racemic ketamine. Ex-vivo electrophysiological recordings indicate that intrinsic and synaptic properties of Layer V pyramidal neurons are not affected by Shank3 genotype or systemic ketamine administration yet they respond to acute application of ketamine and DMT at micromolar concentrations.

Conclusions: We defined a panel of neuroanatomical and functional assays to characterize synaptic pathology in the Shank3 ASD mouse model. The phenotypes we investigated are closely related to the genetic alteration underlying the pathology and thus represent optimal readouts to probe the efficacy of compounds with neurogenic potential, such as ketamine, 2,5-Dimethoxy-4-iodoamphetamine, and N, N-dimethyltryptamine. Preliminary results suggest that ketamine ameliorates the defect caused by Shank3 ablation.