Synaptic Function and Sensory Processing in ZDHHC9-Associated Neurodevelopmental Disorder: A Mechanistic Account

Area of Science:

• Neuroscience
• Computational Biology
• Genetics

Background:

• Loss-of-function variants in ZDHHC9 gene are linked to X-linked intellectual disability (XLID), rolandic epilepsy (RE), and developmental language disorders.
• Understanding the neural mechanisms underlying ZDHHC9-associated neurodevelopmental conditions is crucial for targeted interventions.

Purpose of the Study:

• To investigate the neural mechanisms underlying ZDHHC9-associated differences in cortical function and cognition.
• To integrate human neurophysiological data with computational modeling to explain ZDHHC9's impact.

Main Methods:

• Magnetoencephalography (MEG) was used to record auditory-evoked fields (AEFs) and magnetic mismatch negativity (mMMN) in individuals with ZDHHC9 variants and controls.
• A recurrent neural network (RNN) model was developed to simulate auditory-evoked responses and test the effects of synaptic dysfunction.

Main Results:

• Individuals with ZDHHC9 variants exhibited larger amplitude and later peak latency in AEFs, along with increased mMMN amplitude, indicating altered neural processing.
• RNN model simulations demonstrated that reducing inhibitory synaptic weights recapitulated the observed group differences in evoked responses.
• Strengthening excitatory connections did not yield similar results, supporting the role of reduced inhibition.

Conclusions:

• Reduced neural inhibition is a likely mechanism explaining ZDHHC9 loss-of-function effects on cortical dynamics during sensory processing.
• These findings provide a potential neural basis for ZDHHC9-associated neurodevelopmental conditions.