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Hearing loss and schizophrenia-relevant cortical and behavioral abnormalities in a mouse model of 22q11.2 deletion syndrome

Zinnamon, Fhatarah A.; (2019) Hearing loss and schizophrenia-relevant cortical and behavioral abnormalities in a mouse model of 22q11.2 deletion syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Zinnamon PhD Thesis UCL NIMH Hearing Loss and Schizophrenia-Relevant Cortical and Behavioral Abnormalities in a Mouse Model of 22q11.2 Deletion Syndrome Corrected e thesis signature removed.pdf
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Abstract

Patients with 22q11.2 Deletion Syndrome (22q11DS) have a 25-30% chance of developing schizophrenia and exhibit high rates of conductive hearing loss (HL). HL has been identified as a risk factor for schizophrenia, but the reasons for this association---and its relevance to developmental neuro-behavioral abnormalities in 22q11DS---are unknown. In this thesis, I used the Df1/+ mouse model of 22q11DS to investigate interactions between genetic risk for schizophrenia, HL, and brain and behavioral abnormalities. Df1/+ mice have a multi-gene deletion analogous to human 22q11DS and ~60% of animals display conductive HL. First, I asked whether genotype, HL or both affect sensorimotor gating, cortical auditory evoked potentials (AEPs), or parvalbumin-positive (PV+) inhibitory interneuron density in the primary auditory cortex (A1) using auditory brainstem response measurements (ABRs), prepulse inhibition of the acoustic startle response, auditory evoked potentials (AEPs) and immunohistochemistry. Results indicated that HL in Df1/+ mice was associated with altered central auditory gain, auditory sensorimotor gating and PV+ interneuron density in A1. Next, I characterized the development of HL in Df1/+ mice over postnatal weeks 3-14.6 using ABRs and distortion product otoacoustic emissions. Results showed that HL onset and duration within Df1/+ animals were variable but more likely to be persistent (versus transient), first appearing during postnatal development as opposed to adulthood. Lastly, I investigated the origins of synaptic projections to PV+ interneurons in A1 using modified retrograde rabies virus. Results revealed consistent projection patterns originating within the auditory thalamus and basal forebrain for both anterior and posterior A1 injection locations. This tracing approach holds promise for future experiments comparing projections to PV+ interneurons in wildtype and Df1/+ mice with and without HL. Work presented in this thesis provides evidence for bottom-up neurobiological mechanisms through which HL arising from 22q11DS may promote the emergence of schizophrenia-relevant auditory brain and behavioral abnormalities.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Hearing loss and schizophrenia-relevant cortical and behavioral abnormalities in a mouse model of 22q11.2 deletion syndrome
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Div of Psychology and Lang Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/10072523
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