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In Mice (And Men) Hearing loss (and tinnitus) in mice (and men) Sonja Pyott, Ph.D. Rosalind Franklin Fellow and Assistant Professor Department of Otorhinolaryngology, UMCG Hearing begins in the inner ear Hearing requires sensorineural structures Sensory The hair cells and hair cells auditory neurons are heterogenous! Auditory neurons Brain Hearing requires sensorineural structures Sensory hair cells Auditory Auditory neurons Vestibular Brain Questions my research group asks Sensory 1) What are the molecules hair cells that shape the responses of the sensorineural structures? Auditory neurons Brain Questions my research group asks Sensory • Genetic hair cells • Environmental (noise, infections, chemicals) • Age-related Auditory neurons 2) What are the molecules that contribute to loss of these structures? Brain Questions my research group asks Sensory hair cells Auditory neurons 3) How can these molecules be “drugged” to prevent or reverse hearing loss and tinnitus? Brain Mice are an excellent model system • Similar anatomy and physiology • Shared molecules (genes) • Molecules (genes) can be altered 1.8 cm Mice are an excellent model system Molecule Cell Circuit Systems Genetic Single cell Whole animal Histology techniques physiology physiology Mice are an excellent model system Molecule Cell Circuit Systems Fundamental Research Pre-clinical Validation Academic background Academic background • BS in Biochemistry and Molecular Biology, Penn State University Academic background • Fulbright Scholar and Max Planck Fellow , Max-Planck-Institute for Biophysical Chemistry Academic background • PhD in Neuroscience, Stanford University School of Medicine The isolated auditory and vestibular sensory epithelia The organ of Corti BK channels in cochlear inner hair cells BK KO (Pyott et al., 2004; Pyott et al., 2007) Academic background • Postdoctoral Fellow, Johns Hopkins School of Medicine • Assistant Professor, University of North Carolina Wilmington • Dynamics of glutamate in the synaptic cleft • Organization of the PSD • Excitability of the afferent neuron dendrites • Input from efferents (Reijntjes and Pyott, 2016) ? Life as an expat researcher • Where in Holland is the Netherlands? • What language do they speak in Holland? In the Netherlands? • Do they really eat fries with mayonnaise? Large scale screening for ion channels (and other molecules) that regulate sensorineural structures 24 ion channels 106 ion channels (pore- 8 SLO ion channels 3 ion channels (2 (subclass of forming and regulatory (subclass of pore-forming and 1 voltage-gated K+ subunits) expressed in voltage-gated K+ regulatory subunit) and the cochlea channels) identified Na+ channels) Voltage-gated (73) SLO1-3 (8) SLO1* SLO1* K+ channels (32) • KCNT1/2 are SLO1β1/KCNMB1Na+- SLO2.1/KCNT2 + activated K+ channels Na channels (8) KV1-3 (8) SLO1β2/KCNMB2 SLO2.2/KCNT1 Ca2+ channels (20) • KCNT1/2 are SLO1β3/KCNMB3present in SLO1β3/KCNMB3 the auditory neurons Other (13) NaV1 (8) SLO1β4/KCNMB4 Ligand-gated (9) • KCNT1/2 DKO SLO2.1/KCNT2mice are Other (24) available SLO2.2/KCNT1 SLO3/KCNU1 Auditory brainstem responses (ABRs) in mice 90 dB Sensory inner Δ 5 dB hair cells Auditory Threshold of hearing neurons (40 dB SPL) 20 dB ABR wave I thresholds are similar in WT and KCNT1/2 DKO mice WT KCNT1/2 DKO Auditory brainstem responses (ABRs) in mice 90 dB Sensory inner Δ 5 dB hair cells Auditory Threshold of hearing neurons (40 dB SPL) 20 dB ABR wave I thresholds are similar in WT and KCNT1/2 DKO mice WT KCNT1/2 DKO WT DKO ABR wave I suprathreshold amplitudes are reduced in KCNT1/2 DKO mice WT KCNT1/2 DKO WT DKO KCNT1/2 DKO mice how hidden hearing loss… Hair cell and synapse numbers are similar in KCNT1/2 DKO mice (Wichmann, 2015) KCNT1/2 DKO mice how hidden hearing loss without synapse loss. Spiral ganglion neuron properties are altered in KCNT1/2 DKO mice Loss of KCNT1/2 decreases neuronal AP amplitudes and thresholds. Hidden hearing loss Hearing loss Tinnitus • Can KCNT1/2 DKO mice provide insight into the transition from hidden to overt hearing loss? • Apply similar approaches to identify the molecular mechanisms underlying changes in excitability associated with tinnitus • Relate well-characterized forms of peripheral hearing loss to tinnitus subtypes • Identify genetic mechanisms that contribute to tinnitus Acknowledgements • Marcel van Tuinen, Hao Feng, Daniël Reijntjes, Nick Schubert • Paul Fuchs and Elisabeth Glowatzki (Johns Hopkins University) • Chris Lingle (Washington University in St. Louis), Ebenezer Yamoah (University of Nevada, Reno) • Funding: NOHR, DRF, AAA, NCBC, and UNCW, UMCG, Daiicho Sankyo, TIN-ACT.
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