Age-dependent deficits of auditory brainstem responses in juvenile Neurexin1α knockout rats

Abnormal sensory processing is core to neuropsychiatric and neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders. Developing efficient therapies requires understanding the basic sensory pathways and identifying circuit abnormalities during early development. Auditory brainstem responses (ABRs) are well-established biomarkers for auditory processing on the brainstem level. Beyond their advantage of being easily applicable in clinics (given their non-invasive nature), ABRs have high reproducibility in rodents and translate well to humans (e.g. wave identity), despite species differences (e.g. wave features). We hypothesized that ABRs would reveal sensory abnormalities in neurodevelopmental models with construct validity, such as Neurexin1α knockout (Nrxn1α KO) rats during their development. In a previous study, adult Nrxn1α KO rats showed altered cortical auditory-evoked potentials and impaired prediction error to auditory stimuli (Janz in Transl Psychiat, 12:455, 2022). This study used ABR measurements to assess brainstem physiology during auditory processing in Nrxn1α KO rats and their wild-type littermates. Therefore, we followed the development trajectories of ABRs from the age of 3 weeks to 12 weeks longitudinally. We found that juvenile Nrxn1α KO rats (3 weeks of age) show altered ABRs, which normalized during further development. This alteration was confined to increased latency in waves II, III, and IV of the ABRs, suggesting impaired auditory processing on the level of the superior olivary complex and inferior colliculus. In conclusion, our results suggest that early but transient deficits in the processing of auditory information on the level of the brainstem are present in Nrxn1α KO rats, which may contribute to later cortical auditory processing deficits observed in adulthood. Our study emphasizes the value of ABRs as a functional readout of auditory brainstem circuit function with potential value as a translational biomarker.