Neurexin1α knockout rats display oscillatory abnormalities and sensory processing deficits back-translating key endophenotypes of psychiatric disorders

Abstract

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.

Bridging the translational gap: what can synaptopathies tell us about autism?

“…In a study using an analogue of positron emission tomography (PET) in Nrxn1α+/− mice, prefrontal cortex hypometabolism and dorsal raphe nucleus hypermetabolism were reported, which also correlated with enhanced novel discrimination of odors and longer latency to make correct choices, respectively, (Hughes et al, 2022). In NRXN1 knockout rats, altered cortico-thalamic-striatal circuit communication has also been reported, along with altered gamma band oscillations (Janz et al, 2022). Importantly, this has been linked with developmental delay in autism, and may reflect an E/I imbalance (Orekhova et al, 2007).…”

Circuit-level theories for sensory dysfunction in autism: convergence across mouse models

“…Oscillations have been studied less in mouse models of ASD. Divergent effects on gamma power in the auditory cortex have been reported, from reduced ( 138 , 144 , 145 ), to increased ( 146 ), to not different from wild type ( 147 ). Some studies have reported that gamma phase locking is impaired ( 138 , 144 , 145 ).…”

The ‘PSILAUT’ protocol: an experimental medicine study of autistic differences in the function of brain serotonin targets of psilocybin

“…To do this, we have developed a ‘“shiftability” paradigm [ 17 ] to examine how ‘foundational’ mechanisms of brain function such as neural responses to sensory stimuli or whole-brain network connectivity captured using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are modulated by targeted pharmacological probes. These measures are biologically informative and may be used across a wide range of ages and, in many cases, also back-translate to animal models to inform future target identification and engagement studies [ 18 – 23 ].…”