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 #
5R01DC007905-08
Application #
8429374
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
2013-03-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$372,930
Indirect Cost
$122,654
Name
University of Pittsburgh
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
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
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
Middleton, Jason W; Kiritani, Taro; Pedersen, Courtney et al. (2011) Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proc Natl Acad Sci U S A 108:7601-6
Doiron, Brent; Zhao, Yanjun; Tzounopoulos, Thanos (2011) Combined LTP and LTD of modulatory inputs controls neuronal processing of primary sensory inputs. J Neurosci 31:10579-92
Zhao, Yanjun; Tzounopoulos, Thanos (2011) Physiological activation of cholinergic inputs controls associative synaptic plasticity via modulation of endocannabinoid signaling. J Neurosci 31:3158-68
Zhao, Yanjun; Rubio, Maria E; Tzounopoulos, Thanos (2009) Distinct functional and anatomical architecture of the endocannabinoid system in the auditory brainstem. J Neurophysiol 101:2434-46
Tzounopoulos, Thanos; Kraus, Nina (2009) Learning to encode timing: mechanisms of plasticity in the auditory brainstem. Neuron 62:463-9
Tzounopoulos, Thanos (2008) Mechanisms of synaptic plasticity in the dorsal cochlear nucleus: plasticity-induced changes that could underlie tinnitus. Am J Audiol 17:S170-5

Showing the most recent 10 out of 11 publications