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 (KS), a rare multisystem disorder associated with developmental delay and intellectual disability, results from mutations in either KMT2D (KS type 1) or KDM6A (KS type 2), which encode a chromatin-modifying methyltransferase and demethylase, respectively. However, the mechanisms contributing to intellectual disability in KS remain poorly understood. Here, we generated human iPS cells carrying a conditional Cre/lox-dependent KMT2D or KDM6A loss-of-function mutation, used for directed differentiation into inhibitory or excitatory neurons. Analysis of Cre-mediated induction of KS type 1 and KS type 2 in inhibitory neurons unexpectedly revealed an increase in GABAergic synapse development. Mutant excitatory neurons, however, displayed a reduction in synapse development and impaired information transfer within neural networks. We confirmed these findings in hippocampal neurons in vitro and in vivo using a mouse model for KS type 1. Synapse numbers and synaptic transmission in acute brain slices were shifted to increased inhibition/excitation ratio. Thus, our results, using purely inhibitory or purely excitatory human neurons with conditional deletion of KMT2D or KDM6A, and mouse with Kmt2d deletion, reveal a novel disease mechanism of KS and provide a mechanistic explanation for intellectual disability observed in individuals affected by KS highlighting imbalanced excitation to inhibition in neural circuits.