Cochlear Synaptopathy and Neurodegeneration in Hidden and Overt Hearing Loss

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1 Cochlear Synaptopathy and Neurodegeneration in Hidden and Overt Hearing Loss Sharon G. Kujawa Massachusetts Eye and Ear Infirmary Harvard Medical School National Hearing Conservation Association San Antonio, TX February 24, 2017

2 Noise-Induced Threshold Shifts and Cochlear Injury

3 Threshold shifts after noise: Permanent Before exposure Miller, Watson & Covell, 1963

4 Ears with PTS commonly have hair cell loss Loss of hair cells is obvious in days Normal HCs Pre-Exposure Bechara Kachar Missing Swollen OHCs 1 hour Post-Exposure Loss of OHCs eliminates the amplifier & shifts threshold Wang et al Days 1 hour Post-Exposure Post-Exposure

5 Threshold shifts after noise: Temporary Before exposure A benign exposure and a recovered ear Miller, Watson & Covell, 1963

6 Permanent Injury after Recovery from TTS

7 Thresholds recover with permanent neural amplitude declines CBA/CaJ: 8-16 khz, 100 db SPL, 2 16 wk Kujawa and Liberman 2009

8 Consider possible sites of involvement IHCs, cochlear nerve fibers or the synapses that connect them Outer hair cells -cellular motors that amplify motions Inner hair cells --transduce information into electrochemical signals Cochlear nerve fibers - carry signals from IHCs to brain Nelson Kiang IHC synapses - communication conduits between IHCs and ANFs

9 Quantify hair cells, neurons and synapses In the normal ear: every ribbon opposite a terminal and vice versa; Use immunolabeling to see is preand post-synaptic elements 1 ANF communicates with 1 IHC via 1 synapse Control Synaptic ribbons CtBP2 Terminals NF, NKA Receptor patches GluA2 Hair cells Myo VIIa Exposed

10 Cochlear synaptopathy after TTS In the IHC normal afferent ear: synapse fiber synapses counts peak disappear in the middle within of minutes; the cochlea hair cells remain and recover function Permanently interrupts sensory-to-neural communications for subsets of fibers

11 Primary neural degeneration after TTS Spiral Cochlear ganglion nerve cell fibers death retract follows in days slowly (but loss of communication occurred with synapse loss) 2 weeks 6 months

12 Cochlear synaptopathy after noise: Summary naptopathy, with or without permanent threshold shift or hair cell loss, documented in multiple species, for a broad range of exposures

13 Aging vs. Aging After Noise

14 Age-related declines in response amplitudes CBA/CaJ: Good thresholds to ~ 2 years, but neural response declines begin early, progress steadily 12 khz 12 khz

15 Age-related loss of synapses and neurons Synapse loss Synapses is similarly are lost progressive gradually throughout with age the lifespan Proportional to ABR wave I amplitude declines

16 Hair Cell Loss Age-related cochlear neuropathy aging mice, Threshold synapse elevations loss precedes are well hair explained cell loss by and OHC threshold loss shifts Synaptic Loss What if ears are noiseexposed first?

17 Expose, then age: Quantify synapses Noise Synapses produces are lost synapse gradually loss with in age minutes and then exaggerates aging delayed immediate

18 Expose, then age: Quantify ganglion cells Ears that age after synaptopathic noise show exaggerated spiral ganglion cell loss 16 wk unexposed 104 wk unexposed 16 wk Held to 104 wk

19 Expose, then age: Quantify ganglion cells Ears that age after synaptopathic noise show exaggerated spiral ganglion cell loss

20 Cochlear Synaptopathy/Neuropathy in Humans Viana et al., 2015

21 t al 1995 Pace of sensitivity loss, SGN loss is similar in mouse model and in human Humans, mice with no noise history Humans, mice with full complements of HCs CBA/CaJ Human CBA/CaJ

22 Cochlear neuropathy in aging humans Immunostain human temporal bone tissues A 67-yo female with IHC loss only > 20 khz

23 Cochlear neuropathy in aging humans Ganglion cell counts hide the extent of neuropathy

24 ochlear neuropathy in noise-exposed humans UT: Missing neurons outer hair throughout cells at the cochlear base, places with corresponding IHCs present: to imary neural the degeneration noise notch and mixed sensory + neural loss

25 ert Summary If hair cells die, there is permanent threshold shift

26 idden Summary en if thresholds recover, cochlear synapses and nerve fibers can die

27 Summary synapse loss precedes hair cell loss: In exposed ears, synaptopathy is the sign of pathology as dose is increased; in aging, synaptopathy happens as time progresses. hlear synaptopathy is present in every species studied thus far, including human primates and human temporal bones. e its synapse is destroyed, the neuron is functionally disconnected and es no auditory information unless stimulated directly. ptopathy is likely pervasive for various acquired SNHL etiologies, and rs in ears with and without threshold elevations. sholds are not sensitive to this loss until it is extreme; other assays will be ired for diagnosis, and to characterize the health of remaining neurons.

28 Funding: NIH/NIDCD, DoD, ONR Acknowledgements Lab Members Kate Fernandez Penelope Jeffers Collaborators Albert Edge Kumud Lall Steve Micucci Charlie Liberman ravind Parthasarathy Yev Sergeyenko Bill Sewell