Discussion
auditory processing deficits, auditory hallucinations, cognitive deficits, hypofunction, epilepsy-aphasia spectrum disorders, schizophrenia
DISEASE, DISORDERS, DYSFUNCTION, HYPOFUNCTION, CORTEX
The present study assessed shared functional connectivity profiles of pharmacologically and genetically based NMDAR dysfunction by integrating resting state-fMRI data from 146 genotyped patients with schizophrenia and 142 healthy controls, pharmaco-fMRI data from 28 healthy participants, and postmortem whole-brain microarray gene expression data from 6 healthy donors.The schizophrenia-related genetic variant of the NMDAR 2A subunit was associated with functional connectivity changes most resembling the differential pharmacological effect of ketamine versus midazolam. Importantly, this contrast has been shown to better imitate the functional connectivity changes observed in schizophrenia as compared to the more frequently studied difference between ketamine and placebo [The resemblance between connectivity changes related to the genetic variant and the differential effect of ketamine versus midazolam became more pronounced when considering regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons as suggested by the post-mortem gene expression dataset. In our mechanistic model, these regions should indeed reflect E/I imbalance related to hypofunction of NMDARs on parvalbumin-positive interneurons most directly. In this context, we chose GRIN1 instead of GRIN2A as one of our target genes, as GRIN2A expression may be less reliably estimated due to stronger age dependence [From a more functional perspective, shared connectivity changes included hyper-connectivity between the basal ganglia/thalamus and an auditory-sensory-motor network as well as hypo-connectivity between auditory and visual regions. Increased functional connectivity between the thalamus and the auditory-sensory-motor (ASM) network is one of the most consistent findings which are shared by resting state-fMRI studies on schizophrenia and pharmaco-fMRI studies using ketamine [Hypo-connectivity between auditory and visual regions mainly involved the superior temporal gyrus on the one hand and the fusiform and lateral occipital cortex on the other hand. Basic auditory processing deficits as assessed by behavioral, EEG or fMRI experiments, represent a consistent finding in patients with schizophrenia which may contribute to auditory hallucinations, higher-order cognitive deficits, and particularly language dysfunction [Besides pure activation deficits to different auditory stimulation paradigms in patients [On a behavioral level, the schizophrenia-related GRIN2A variant was associated with language-related negative symptomatology. Importantly, language dysfunction is considered a disease defining symptom both of schizophrenia and disorders related to exonic variants of GRIN2A (epilepsy-aphasia spectrum disorders) [