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

## TL;DR

This study explores how ZDHHC9 gene variants affect brain function by combining human brain data with a computational model, suggesting reduced inhibition may explain sensory processing differences.

## Contribution

The study provides a mechanistic account linking ZDHHC9 variants to altered cortical function through computational modeling of synaptic dysfunction.

## Key findings

- Reduced inhibition in a neural network model recapitulates increased auditory response amplitudes and delayed latencies seen in ZDHHC9 individuals.
- Strengthening excitatory connections did not produce stable activity or realistic auditory responses in the model.
- The findings suggest that ZDHHC9-associated synaptic dysfunction impacts sensory processing via altered inhibition.

## Abstract

Loss‐of‐function ZDHHC9 variants are associated with X‐linked intellectual disability (XLID), rolandic epilepsy (RE) and developmental language difficulties. This study integrates human neurophysiological data with a computational model to identify a potential neural mechanism explaining ZDHHC9‐associated differences in cortical function and cognition. Magnetoencephalography (MEG) data was collected during an auditory roving oddball paradigm from eight individuals with a ZDHHC9 loss‐of‐function variant (ZDHHC9 group) and seven age‐matched individuals without neurological or neurodevelopmental difficulties (control group). Auditory‐evoked fields (AEFs) were larger in amplitude and showed a later peak latency in the ZDHHC9 group but demonstrated normal stimulus‐specific properties. Magnetic mismatch negativity (mMMN) amplitude was also increased in the ZDHHC9 group, reflected by stronger neural activation during deviant processing relative to the standard. A recurrent neural network (RNN) model was trained to mimic group‐level auditory‐evoked responses, and subsequently perturbed to test the hypothesised impact of ZDHHC9‐driven synaptic dysfunction on neural dynamics. Results of model perturbations showed that reducing inhibition levels by weakening inhibitory weights recapitulates the observed group differences in evoked responses. Stronger reductions in inhibition levels resulted in increased peak amplitude and peak latency of RNN prediction relative to the pre‐perturbation predictions. Control experiments in which excitatory connections were strengthened by the same levels did not result in consistently stable activity or AEF‐like RNN predictions. Together, these results suggest that reduced inhibition is a plausible mechanism by which loss of ZDHHC9 function alters cortical dynamics during sensory processing.

In the current study, we employed a bottom‐up approach to study the impact of synaptic‐level alterations associated with ZDHHC9 variants on cortical function in healthy and ZDHHC9‐deficient participants. To achieve this, a recurrent neural network model was employed to recapitulate MEG‐derived auditory‐evoked responses and subsequently perturbed in order to determine effects on resulting dynamics. We showed that reduced network inhibition recapitulates trends observed empirically, specifically increased response amplitudes, delayed peak latencies and increased mismatch negativity. These results offered a mechanistic account on the impact of ZDHHC9‐associated synaptic alterations on auditory processing.