Tonotopy, the orderly representation of sound frequency is a fundamental organizing principle of the auditory system. However, the mechanisms by which precise tonotopy is established in the developing brain are poorly understood. The long term goal of this research program is to elucidate these mechanisms in the lateral superior olive, a primary sound localization nucleus in the auditory brainstem of mammals. Previous studies on the development of the two major afferent pathways to the LSO, the excitatory pathway from the cochlear nucleus (CN) and the inhibitory pathway from the medial nucleus of the trapezoid body (MNTB), indicate that tonotopic refinement of the inhibitory MNTB-LSO pathway involves three major steps - synaptic silencing, synaptic strengthening, and axonal pruning. Each of these processes occurs during a distinct developmental period which is characterized by distinct synaptic properties and activity patterns. We hypothesize that these transient properties are crucial for the implementation of specific refinement steps. We propose testing this hypothesis by delineating the role of the transition from depolarizing to hyperpolarizing responses at MNTB-LSO synapses and activity-dependent synaptic plasticity at excitatory CN-LSO synapses. To achieve these goals we will employ a combination of physiological and anatomical techniques that will be applied to brainstem slices prepared from neonatal and juvenile wild-type and genetically altered mice. Specifically, we will use whole-cell recordings to characterize the development of synaptic properties and synaptic plasticity, focal photolysis of caged glutamate to map functional connectivity between the MNTB and LSO, and reconstruction and quantitative analysis of single MNTB axon terminal fields. Results from these studies will provide important insight into the cellular and synaptic mechanisms that govern tonotopic refinement in the mammalian brain. Detailed information about these mechanisms is essential to the understanding of the biological and developmental basis of human auditory processing deficits, including deficits in speech perception or developmental dyslexia, that are associated with abnormal auditory processing on the level of the auditory brainstem.

Public Health Relevance

This research is aimed to provide insight into the cellular mechanisms by which precise neuronal connections in the mammalian auditory system become established during development. Information about these mechanisms is important for understanding the cause of auditory processing deficits that are associated with developmental dyslexia, impairments in speech perceptions, and autism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004199-15
Application #
8468673
Study Section
Special Emphasis Panel (ZRG1-IFCN-T (02))
Program Officer
Platt, Christopher
Project Start
1999-08-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$511,074
Indirect Cost
$157,882
Name
University of Pittsburgh
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Clause, Amanda; Kim, Gunsoo; Sonntag, Mandy et al. (2014) The precise temporal pattern of prehearing spontaneous activity is necessary for tonotopic map refinement. Neuron 82:822-35
Altieri, Stefanie C; Zhao, Tianna; Jalabi, Walid et al. (2014) Development of glycinergic innervation to the murine LSO and SPN in the presence and absence of the MNTB. Front Neural Circuits 8:109
Saadi, R A; He, K; Hartnett, K A et al. (2012) SNARE-dependent upregulation of potassium chloride co-transporter 2 activity after metabotropic zinc receptor activation in rat cortical neurons in vitro. Neuroscience 210:38-46
Kim, Gunsoo; Kandler, Karl (2011) Paired recordings from distant inhibitory neuron pairs by a sequential scanning approach. J Neurosci Methods 200:185-9
Clause, Amanda; Nguyen, Tuan; Kandler, Karl (2011) An acoustic startle-based method of assessing frequency discrimination in mice. J Neurosci Methods 200:63-7
Castro, Jason B; Kandler, Karl (2010) Changing tune in auditory cortex. Nat Neurosci 13:271-3
Noh, Jihyun; Seal, Rebecca P; Garver, Jessica A et al. (2010) Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nat Neurosci 13:232-8
Kim, G; Kandler, K (2010) Synaptic changes underlying the strengthening of GABA/glycinergic connections in the developing lateral superior olive. Neuroscience 171:924-33
Stensrud, Kenneth; Noh, Jihyun; Kandler, Karl et al. (2009) Competing pathways in the photo-Favorskii rearrangement and release of esters: studies on fluorinated p-hydroxyphenacyl-caged GABA and glutamate phototriggers. J Org Chem 74:5219-27
Kandler, Karl; Clause, Amanda; Noh, Jihyun (2009) Tonotopic reorganization of developing auditory brainstem circuits. Nat Neurosci 12:711-7

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