Disentangling Genetic and Experiential Risk Factors for Cortical Abnormalities in a Mouse Model of Schizophrenia

How do genes and experience interact to cause psychiatric disease? Answering this question is one of the greatest challenges for neuroscience and mental health research. Here, we will leverage a unique experimental system we have established in mice to disentangle effects of genetic and experiential risk factors for schizophrenia on the brain. More specifically, we aim to understand how genetic vulnerability to schizophrenia and experience of hearing impairment interact to cause abnormalities in cortical function.

Hearing impairment has been called the "neglected risk factor for psychosis". Longitudinal studies have linked early hearing impairment with later schizophrenia diagnosis, and adulthood hearing impairment with subsequent psychotic experiences including auditory hallucinations. The mechanisms underlying these longitudinal associations are unknown, but could include common causes of both hearing impairment and psychosis, or causal effects of experience of hearing impairment on the brain. A causal role for hearing impairment in emergence of auditory hallucinations is mechanistically plausible, because the experience of hearing impairment is known to increase spontaneous and correlated activity of neurons in the auditory brain. Moreover, changes in cortical function caused by experience of hearing impairment resemble disruptions of cortical excitation and inhibition that have also been observed in schizophrenia patients and in animal models of schizophrenia.

Could experience of hearing impairment exacerbate cortical abnormalities arising from genetic vulnerability to schizophrenia, acting as a "second hit" for psychiatric disease? Or do genetic vulnerability to schizophrenia and experience of hearing impairment have largely independent, non-overlapping effects on cortical function?

We propose to perform the first rigorous experimental test of these two possibilities, using a mouse model of human 22q11.2 Deletion Syndrome (22q11.2DS). The 22q11.2 chromosomal microdeletion is one of the most significant known genetic risk factors for schizophrenia, and in some cases, also causes middle-ear problems that reduce hearing ability. Thus, some 22q11.2DS patients have normal hearing while others have mild to moderate hearing impairment. We have previously shown that just like 22q11.2DS patients, 22q11.2DS model mice can have either normal hearing or mild to moderate hearing impairment from middle-ear problems. Here, we will examine how measures of cortical function vary with hearing ability across individual 22q11.2DS model mice, to determine the relationship between brain abnormalities and hearing impairment in the presence of genetic vulnerability to schizophrenia. We will also examine how the same measures of cortical function vary with hearing ability across genetically normal (wildtype) mice with normal hearing or experimentally induced mild to moderate hearing impairment. Comparing results between 22q11.2DS model mice and wildtype mice will enable us to distinguish between independent and synergistic effects of genotype and hearing impairment.

The main expected outcome of this project is a breakthrough in understanding how cortical dysfunction arises from genetic and experiential risk factors for schizophrenia. If genetic vulnerability to schizophrenia and experience of hearing impairment have largely independent, non-overlapping effects on cortical function, then the contrast between the two effects will help to define the cortical consequences of genetic risk for schizophrenia (and experience of hearing impairment) more clearly. Conversely, if experience of hearing impairment exacerbates cortical abnormalities arising from genetic vulnerability to schizophrenia, then the experiments will provide mechanistic evidence that hearing impairment may be a causal contributor to psychiatric disease.

Breakthroughs in mechanistic understanding of psychiatric disease require insight into how genes and experience interact to disrupt brain function. Hearing impairment is a risk factor for auditory hallucinations and schizophrenia, with odds ratios of 3 in meta-analysis of longitudinal studies. The mechanisms of this longitudinal association are unknown but may include causal effects of hearing impairment on cortical circuitry. Here, we will use a mouse model of 22q11.2 Deletion Syndrome (22q11.2DS) to investigate whether experience of hearing impairment exacerbates brain abnormalities arising from genetic risk for schizophrenia.

The 22q11.2 chromosomal microdeletion is one of the strongest genetic risk factors for schizophrenia; 30% of 22q11.2DS patients develop schizophrenia in adulthood. Up to 60% also have early-onset middle-ear problems causing mild to moderate hearing impairment, while at least 40% have normal hearing. In previous work, we have proven that a mouse model of 22q11.2DS replicates the large inter-individual differences in hearing ability observed among 22q11.2DS patients.

We will exploit the inter-individual differences in hearing ability among genetically identical 22q11.2DS model mice to analyse how measures of cortical function vary with hearing ability in the context of genetic vulnerability to schizophrenia. We will also analyse how cortical measures vary with hearing ability in wildtype siblings of 22q11.2DS model mice with experimentally induced hearing impairment. Measures of cortical function will include neuronal population activity in auditory cortex and frontal cortex; EEG signals; auditory behaviour; and cortical cell distributions. Comparisons between 22q11.2DS model mice and wildtype mice will reveal whether genetic vulnerability to schizophrenia and experience of hearing impairment are independent or synergistic risk factors for cortical dysfunction, providing pre-clinical data for future investigations in 22q11.2DS patients.