Shank3Bpathophysiology: Early metformin treatment rescues behavioural deficits and normalises exacerbated mRNA translation.

Abstract

Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder associated with autism spectrum disorder and intellectual disability, is caused by either deletions in human chromosome 22q13 or mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. PMS is highly debilitating, and existing treatments are ineffective. SHANK3 interacts with at least 3 synaptic receptors through synaptic-associated proteins, some of which are upstream of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathways. Metformin, an inhibitor of the mTORC1 and MAPK/ERK signalling pathways, was shown to correct core phenotypes in a fragile X mouse model, offering therapeutic potential for PMS. Male Shank3B, a PMS mouse model, and wild-type mice were treated from birth with metformin (5 mg/mL) or vehicle. Shank3Bmice displayed increased self-grooming, decreased social interaction, reduced duration and frequency of ultrasonic vocalisations, and impaired hippocampal-dependent memory. Upregulated mTORC1 activity was observed in the hippocampus and prefrontal cortex, along with decreased synaptosomal protein expression in the striatum of GluN2B (an N-methyl-d-aspartate receptor (NMDAR) subunit), Homer1 (a synaptic-associated protein) and GluA2 (an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit), all of which interact with Shank3. Metformin treatment from birth corrected core behavioural impairments, exaggerated mRNA translation, and decreased striatal synaptic protein expression. Considering its exceptional safety profile, metformin is a promising therapeutic option for a rapid clinical translation of PMS treatment.