The dorsal cochlear nucleus (DCN) is an auditory brainstem center that integrates auditory signals with multimodal sensory signals thought to aid in orientation to sounds of interest. Our previous studies have identified a number of novel mechanisms of synaptic plasticity in the DCN and have uncovered their influence in the processing of auditory nerve inputs. Here, we propose to investigate the physiological role of an """"""""unconventional neurotransmitter"""""""" that is coreleased with glutamate. DCN parallel fiber terminals contain uniquely high levels of Zn[2+] in their gluatamatergic synaptic vesicles. However, the physiological significance of synaptic Zn[2+] release is completely unknown for the auditory system and remains poorly understood for other brain areas. We hypothesize that synaptically released Zn[2+] is a neurotransmitter in the auditory system that regulates the intrinsic and synaptic properties of DCN neurons. To test this hypothesis we will employ a combination of physiological, anatomical and biochemical techniques that will be applied to brainstem slices prepared from wild type and genetically modified mice. Elucidating the mechanisms and the roles of this novel neurotransmitter system will contribute significantly towards the understanding of synaptic and intrinsic mechanisms that are involved during normal and pathological auditory processing.

Public Health Relevance

This research is aimed to provide insight into the mechanisms via which synaptic Zn[2+], an unconventional neurotransmitter that is coreleased with glutamate, regulates the intrinsic and synaptic properties of auditory neurons. Elucidating the mechanisms and the roles of this novel neurotransmitter system will contribute significantly towards the understanding of synaptic and intrinsic mechanisms that are involved during normal and pathological auditory processing.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC007905-07
Application #
8291685
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Cyr, Janet
Project Start
2005-12-01
Project End
2017-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
7
Fiscal Year
2012
Total Cost
$392,557
Indirect Cost
$129,109
Name
University of Pittsburgh
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ceballos, Cesar C; Li, Shuang; Roque, Antonio C et al. (2016) Ih Equalizes Membrane Input Resistance in a Heterogeneous Population of Fusiform Neurons in the Dorsal Cochlear Nucleus. Front Cell Neurosci 10:249
Perez-Rosello, Tamara; Anderson, Charles T; Ling, Cindy et al. (2015) Tonic zinc inhibits spontaneous firing in dorsal cochlear nucleus principal neurons by enhancing glycinergic neurotransmission. Neurobiol Dis 81:14-9
Joshi, Ankur; Middleton, Jason W; Anderson, Charles T et al. (2015) Cell-specific activity-dependent fractionation of layer 2/3→5B excitatory signaling in mouse auditory cortex. J Neurosci 35:3112-23
Li, Shuang; Kalappa, Bopanna I; Tzounopoulos, Thanos (2015) Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus. Elife 4:
Kalappa, Bopanna I; Anderson, Charles T; Goldberg, Jacob M et al. (2015) AMPA receptor inhibition by synaptically released zinc. Proc Natl Acad Sci U S A 112:15749-54
Anderson, Charles T; Radford, Robert J; Zastrow, Melissa L et al. (2015) Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc. Proc Natl Acad Sci U S A 112:E2705-14
Perez-Rosello, Tamara; Anderson, Charles T; Schopfer, Francisco J et al. (2013) Synaptic Zn2+ inhibits neurotransmitter release by promoting endocannabinoid synthesis. J Neurosci 33:9259-72
Li, Shuang; Choi, Veronica; Tzounopoulos, Thanos (2013) Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus. Proc Natl Acad Sci U S A 110:9980-5
Leao, Ricardo M; Li, Shuang; Doiron, Brent et al. (2012) Diverse levels of an inwardly rectifying potassium conductance generate heterogeneous neuronal behavior in a population of dorsal cochlear nucleus pyramidal neurons. J Neurophysiol 107:3008-19
Zhao, Yanjun; Rubio, Maria; Tzounopoulos, Thanos (2011) Mechanisms underlying input-specific expression of endocannabinoid-mediated synaptic plasticity in the dorsal cochlear nucleus. Hear Res 279:67-73

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