Human and Mouse Models for Kabuki Syndrome Reveal Increase in Inhibitory Synapse Development

Intellectual disability, affecting 2-3% of the general population, often coincides with neurodevelopmental disorders and is frequently caused by mutations that impair synaptic function. Kabuki syndrome, a rare multisystem disorder associated with developmental delay and intellectual disability, results from mutations in either KMT2D (type 1) or KDM6A (type 2), which encode a chromatin-modifying methyltransferase and demethylase, respectively. However, the mechanisms contributing to intellectual disability in Kabuki syndrome remain poorly understood. In this study, we investigated synapse development in neurons using both in vitro human models of Kabuki syndrome types 1 and 2, as well as an in vivo mouse model of Kabuki syndrome type 1. Our findings revealed that both mature human iPSC-derived neurons and mice harboring disease-causing mutations exhibited increased inhibitory synapse development. This synaptic imbalance led to impaired excitatory information transfer within neural networks, which may underlie the cognitive deficits observed in Kabuki syndrome.