Human Neuron and Mouse Models Reveal Synaptic Imbalance in Kabuki Syndrome.

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Intellectual disability affects 2-3% of the population, often linked to synaptic dysfunction.
• Kabuki syndrome (KS), caused by mutations in chromatin regulators KMT2D (KS1) and KDM6A (KS2), is associated with developmental delay and intellectual disability.
• The precise mechanisms underlying intellectual disability in KS are not well understood.

Purpose of the Study:

• To investigate the synaptic and cellular mechanisms contributing to intellectual disability in Kabuki syndrome.
• To elucidate the role of KMT2D and KDM6A mutations in neuronal development and function.
• To establish a mechanistic link between chromatin remodeling defects and disrupted neural information transfer in KS.

Main Methods:

• Generated human induced pluripotent stem cells (iPSCs) with conditional loss-of-function mutations in KMT2D or KDM6A.
• Differentiated iPSCs into excitatory and inhibitory neurons for in vitro analysis.
• Utilized a KMT2D-mutant mouse model (KS1) for in vivo validation and analysis of hippocampal neurons and brain slices.
• Investigated astrocytic function and neuroinflammatory signaling pathways.

Main Results:

• KS1 and KS2 human neurons exhibited increased inhibitory (GABAergic) synapse formation and decreased excitatory synapse development.
• The KS1 mouse model showed a conserved excitation-inhibition imbalance with increased inhibitory and decreased excitatory synapses.
• Synaptic transmission was impaired, with an increased inhibition-to-excitation ratio observed in brain slices.
• KS1 mutations activated neuroinflammatory signaling and impaired astrocytic function, promoting glia-driven inhibitory synapse formation.

Conclusions:

• KMT2D/KDM6A mutations cause a synaptic imbalance characterized by increased inhibition and decreased excitation, contributing to intellectual disability in KS.
• This study provides the first mechanistic framework linking chromatin remodeling defects to synaptic dysfunction and altered neural circuit activity in KS.
• Glial contributions to disease pathogenesis were uncovered, suggesting potential therapeutic targets for restoring synaptic balance in KS.