Hypersynchronous iPSC-derived SHANK2 neuronal networks are rescued by mGluR5 agonism

Variants in the SHANK2 gene, linked to neurodevelopmental disorders like autism, were studied using human iPSC-derived neurons and multielectrode arrays. We compared two isogenic pairs of SHANK2 cell lines and found that SHANK2 networks exhibited a hyperconnectivity phenotype at the network level. These networks showed a significantly increased frequency and reduced duration of network burst events compared to controls. SHANK2 network activity was hypersynchronous, with stronger functional correlations between recording channels. Spikes within SHANK2 network bursts formed high-frequency trains, creating a distinctive burst shape. Calcium-dependent reverberating super bursts (RSBs) were common in control networks but rare in SHANK2 networks. Treatment with the group 1 mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) fully rescued SHANK2 network hypersynchrony, restored RSB detection, and improved network burst frequency and duration. The findings demonstrate that SHANK2 variants cause functional hyperconnectivity, which can be rescued by pharmacologically regulating glutamatergic neurotransmission.