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

Abstract

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.

Keywords: Auditory brainstem responses; Autism spectrum disorders; Biomarkers; Neurexins; Neurodevelopmental disorders; Non-invasive brain technology; Schizophrenia.

Fig. 1

Comparison of ABR waveforms between Nrxn1α KO and wild-type littermate rats during development. ABR waveforms across the stimulus intensities 90, 70, and 50 dB from each tested time point; starting with week 3 (A), week 4 (B), week 6 (C), (WT: N = 15, KO: N = 15), week 8 (D), and week 12 (E); (WT: N = 15, KO: N = 14). Recordings from the WT are in blue and Nrxn1α KO in red. Unpaired CBPT revealed significant differences between clusters following 1000 permutations (p < 0.05) and displayed in Black bars above the graphs. The Gray bars indicate clusters that have not reached a significant threshold post-permutation. Data displayed as mean ± SEM.

Fig. 2

Hearing sensitivity is similar between Nrxn1α KO and wild-type littermate rats during the development. (A) Schematic illustrating the area-under-the-curve AUC of wave I (P1 AUC) used to assess hearing sensitivity. (B, C) Quantitative analysis of P1 AUC across stimulus intensities for Nrxn1α KO (in red) and wild-type (in blue) rats; at 3 weeks (B), at 4 weeks (C), at 6 weeks (D) (WT: N = 15, KO: N = 15), at 8 weeks (E), and 12 weeks of age (F) (WT: N = 15, KO: N = 14). Data displayed as mean ± SEM. Two-way mixed ANOVA, with Sidak’s post-test, *p < 0.05.

Fig. 3

Nrxn1α KO rats show a delay in ABR latency during the early juvenile phase. (A) Absolute latencies for individual ABR waves in 3 week old rats. Nrxn1α KO (in red) and wild-type (in blue) rats. (B) Absolute latencies for individual ABR waves across all measured time points (Week 3–6 WT: N = 15, KO: N = 15)) (Week 8–12 (WT: N = 15, KO: N = 14)), each data point represents the averaged ABR wave latency. (C) Interpeak latencies for individual ABR waves in 3 week old rats. (D) Interpeak latencies for individual ABR waves across all measured time points (week 3–6 WT: N = 15, KO: N = 15)) (week 8–12 (WT: N = 15, KO: N = 14)), each data point represents the averaged relative ABR wave latency. Two-way mixed ANOVA, with Tukey’s post-test, revealed statistically significant differences between the Nrxn1α KO and WT rats. *p < 0.05.