TCF4 Mutations Disrupt Synaptic Function Through Dysregulation of RIMBP2 in Patient-Derived Cortical Neurons

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Genetic variations in the TCF4 gene are associated with developmental and psychiatric conditions, including Pitt-Hopkins syndrome (PTHS).
• TCF4 encodes a transcription factor crucial for neuronal development and function.
• The precise mechanisms by which TCF4 mutations cause pathophysiology in humans remain unclear.

Purpose of the Study:

• To model Pitt-Hopkins syndrome (PTHS) using human cortical neurons.
• To investigate the cellular and molecular mechanisms underlying TCF4-associated neurodevelopmental disorders.
• To identify potential therapeutic targets for PTHS.

Main Methods:

• Differentiated human cortical neurons from induced pluripotent stem cells of PTHS patients and controls.
• Assessed neuronal function using whole-cell electrophysiology, Ca2+ imaging, and multielectrode arrays.
• Utilized immunocytochemistry and RNA sequencing to analyze molecular changes.

Main Results:

• PTHS neurons exhibited deficits in synaptic transmission, network excitability, and homeostatic plasticity.
• Transcriptomic analysis revealed altered expression of presynaptic neurotransmission genes, with RIMBP2 being significantly downregulated.
• Increasing RIMBP2 expression rescued synaptic and network deficits in PTHS neurons.

Conclusions:

• TCF4 is a critical regulator of human synaptic development and plasticity.
• Dysregulation of presynaptic function, specifically RIMBP2, is an early pathological mechanism in PTHS.
• Targeting RIMBP2 may offer a therapeutic strategy for PTHS.