Neurexins are presynaptic transmembrane proteins crucial for synapse development and organization. Deletion and missense mutations in all three Neurexin genes have been identified in psychiatric disorders, with mutations in the NRXN1 gene most strongly linked to schizophrenia (SZ) and autism spectrum disorder (ASD). While the consequences of NRXN1 deletion have been extensively studied on the synaptic and behavioral levels, circuit endophenotypes that translate to the human condition have not been characterized yet. Therefore, we investigated the electrophysiology of cortico-striatal-thalamic circuits in Nrxn1α−/− rats and wildtype littermates focusing on a set of translational readouts, including spontaneous oscillatory activity, auditory-evoked oscillations and potentials, as well as mismatch negativity-like (MMN) responses and responses to social stimuli. On the behavioral level Nrxn1α−/− rats showed locomotor hyperactivity. In vivo freely moving electrophysiology revealed pronounced increases of spontaneous oscillatory power within the gamma band in all studied brain areas and elevation of gamma coherence in cortico-striatal and thalamocortical circuits of Nrxn1α−/− rats. In contrast, auditory-evoked oscillations driven by chirp-modulated tones showed reduced power in cortical areas confined to slower oscillations. Finally, Nrxn1α−/− rats exhibited altered auditory evoked-potentials and profound deficits in MMN-like responses, explained by reduced prediction error. Despite deficits for auditory stimuli, responses to social stimuli appeared intact. A central hypothesis for psychiatric and neurodevelopmental disorders is that a disbalance of excitation-to-inhibition is underlying oscillatory and sensory deficits. In a first attempt to explore the impact of inhibitory circuit modulation, we assessed the effects of enhancing tonic inhibition via δ-containing GABAA receptors (using Gaboxadol) on endophenotypes possibly associated with network hyperexcitability. Pharmacological experiments applying Gaboxadol showed genotype-specific differences, but failed to normalize oscillatory or sensory processing abnormalities. In conclusion, our study revealed endophenotypes in Nrxn1α−/− rats that could be used as translational biomarkers for drug development in psychiatric disorders.

Brain function depends on complex circuit interactions between excitatory and inhibitory neurons embedded in local and long-range networks. Systemic GABAA-receptor or NMDA-receptor modulation alters the excitatory/inhibitory balance (EIB), measurable with electroencephalography (EEG). However, EEG signatures are complex in localization and spectral composition. We developed and applied analytical tools to investigate the effects of two EIB modulators, MK801 (NMDAR-antagonist) and diazepam (GABAAR-modulator), on periodic and aperiodic EEG features in freely-moving male Sprague-Dawley rats. We investigated how, across three brain regions, EEG features are correlated with EIB modulation. We found that the periodic component was composed of seven frequency bands that presented region- and compound-dependent changes. The aperiodic component was also different between compounds and brain regions. Importantly, the parametrization into periodic and aperiodic components unveiled correlations between quantitative EEG and plasma concentrations of pharmacological compounds. MK-801 exposures were positively correlated with the slope of the aperiodic component. Concerning the periodic component, MK-801 exposures correlated negatively with the peak frequency of low-gamma oscillations but positively with those of high-gamma and high-frequency oscillations. As for the power, theta and low-gamma oscillations correlated negatively with MK-801, whereas mid-gamma correlated positively. Diazepam correlated negatively with the knee of the aperiodic component, positively to beta and negatively to low-gamma oscillatory power, and positively to the modal frequency of theta, low-, mid-, and high-gamma. In conclusion, correlations between exposures and pharmacodynamic effects can be better-understood thanks to the parametrization of EEG into periodic and aperiodic components. Such parametrization could be key in functional biomarker discovery.SIGNIFICANCE STATEMENTExcitatory-inhibitory balance (EIB) is compromised in neurological disorders. Our study demonstrates that pharmacologically-induced effects on EIB can be quantified by decomposing the qEEG PS signal into the oscillatory periodic and the 1/f aperiodic components. MK-801 and diazepam showed distinct signatures across brain regions and EEG components. Specific features of these components are sensitive to relatively small changes in measured exposure. This methodological approach and the features identified as sensitive to EIB modulation could be key for the development of new therapies and functional biomarkers in disorders with excitatory-inhibitory imbalance.