Could comorbid hearing impairment be a “second-hit” risk factor for brain abnormalities in 22q11.2 Deletion Syndrome?

Hearing loss has been associated with the development of psychosis and is recognized as a sensory risk factor for multiple psychiatric disorders. Auditory processing dysfunction is commonly observed in psychosis. However, human studies often overlook the hearing sensitivities of participants or focus solely on participants with normal hearing. In our recent publication (https://rdcu.be/d5C8J), we investigated the interplay between hearing loss and genetic risks on brain abnormalities in the common chromosome microdeletion, 22q11.2 Deletion Syndrome (22q11.2DS).
The 22q11.2 deletion is one of the strongest genetic risk factors for multiple psychiatric disorders and also increases the vulnerability to middle-ear infections. Up to 60% of deletion carriers experience hearing impairment, and approximately 30% develop schizophrenia in adulthood. However, it remains unknown whether these two risks interact.
We used the Df1/+ mouse model of the 22q11.2 deletion to investigate how hearing impairment might interact with increased genetic vulnerability to psychiatric disease and affect auditory brain function. We measured brain function using cortical auditory evoked potentials (AEPs), which are commonly measured non-invasively in humans. Peripheral hearing sensitivities were assessed with auditory brainstem responses (ABRs), which reflect auditory nerve activity. We leveraged large inter-individual variation in hearing ability among Df1/+ mice to distinguish the effects of genetic background from the effects of hearing impairment.
Auditory brain compensation for hearing impairments by increasing central gain
The central AEP responses showed less variability between animals with different levels of hearing impairment compared to peripheral ABR responses among Df1/+ mice. The ratio between central AEP amplitudes and peripheral ABR amplitudes indicated compensation of auditory gain along the afferent auditory pathway, which was positively correlated with the severity of hearing loss.
Increased level-dependent AEP growth was robust to hearing impairments in Df1/+ mice
Df1/+ mice exhibited stronger dependence on increasing sound intensity levels, regardless of the presence of hearing impairments. This robust, augmented level-dependent AEP growth reflected increased excitability in subcortical auditory structures and/or the auditory cortex, which could serve as a reliable indicator for detecting genetically related risk factors.
Reduced repetition suppression in Df1/+ mice with normal hearing
Df1/+ mice with normal hearing showed reduced repetition suppression compared to WT mice, particularly at longer intervals. This might reflect normal subcortical adaptation processes but abnormally weak damping of recurrent excitation in the higher auditory cortex.
We hypothesized that both the 22q11.2 deletion and hearing impairment alter auditory cortical excitability and adaptation in similar ways and that auditory brain abnormalities in 22q11.2DS arise from interactions between genetic vulnerability and the central consequences of auditory deafferentation. Hearing impairment is already known to cause increased excitability and decreased inhibitory synaptic transmission in the auditory cortex. Previous work has identified abnormally sparse parvalbumin-expressing (PV) inhibitory interneurons in the auditory cortex of Df1/+ mice. These interneurons play a critical role in auditory cortical gain control, adaptation, and recurrent excitation. Additionally, deficits in inhibitory signaling have been reported in the prefrontal cortex and hippocampus in other mouse models of 22q11.2DS, while human 22q11.2DS cerebral cortical organoids have been found to display increased spontaneous firing.
We conclude that auditory deafferentation and genetic risk for 22q11.2DS can have both independent and interactive effects on evoked-potential measures of auditory brain function. Our results highlight the relevance of comorbid hearing loss to auditory brain dysfunction in 22q11.2DS and identify potential biomarkers for psychiatric disease that are robust to hearing impairment.
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Translational Psychiatry
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