Synaptic function and sensory processing in ZDHHC9-associated neurodevelopmental disorder: a mechanistic account

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). Evoked responses to auditory stimulation 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 recapitulate 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. ![Graphical Abstract][1] Graphical Abstract 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 developed to recapitulate MEG-derived auditory evoked responses and subsequently perturbed in order to determine effects on resulting dynamics. We show that reduced network inhibition recapitulates empirical observations, 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. ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes