The long-term objective of this research is to understand the cellular mechanisms by which neuronal activity exerts its effects on the formation, reorganization, and stabilization of precisely organized neuronal connections.
The aim of the proposed project is to elucidate these mechanisms in the development of tonotopically organized, converging excitatory and inhibitory connections in the auditory brainstem of mammals. Focus will be on the lateral superior olivary nucleus (LSO), a binaural nucleus involved in sound localization, in which tonotopically organized ipsilateral and contralateral glycinergic inputs converge on single cells. Previous studies have shown that glycine and GABA, the inhibitory neurotransmitter in the adult system, are depolarizing in the developing LSO when inhibitory connections are being refined. The applicant will test the hypothesis that the depolarizing action of these inhibitory neurotransmitters represents a novel cellular mechanism for activity-dependent refinement of developing inhibitory synapses. They will use an in vitro brainstem slice preparations from pre- and postnatal rats to determine 1) whether the depolarizing neurotransmitters glycine and GABA increase intracellular calcium concentration in developing LSO neurons, 2) whether depolarizing inhiitory synapses act like excitatory synapses, 3) whether refinement of inhibitory connections in the LSO involves the elimination of functional synapses, and 4) whether depolarizing inhibitory connections in the LSO can express activity-dependent changes in synaptic strength such as LTP and LTD. To achieve these specific aims whole-cell and perforated patch clamp recordings will be combined with single cell tracing, calcium imaging and fast, localized photolytic cleavage of neurotransmitters (photostimulation). The experiments will be important for understanding how neuronal activity participates in the formation and reorganization of auditory circuits involved in sound localization. The proposed research may provide new insights into human communication disorders such as speech perception, specific language impairment and dyslexia that result from impaired auditory processing and that likely have developmental components. Understanding the basic cellular mechanisms that rule the development and plasticity of inhibitory circuits is fundamental for understanding the cause of numerous pathological brain states, including epilepsy, that result from an abnormal organization of inhibitory circuits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004199-03
Application #
6379510
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Luethke, Lynn E
Project Start
1999-08-01
Project End
2006-10-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$193,477
Indirect Cost
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Clause, Amanda; Lauer, Amanda M; Kandler, Karl (2017) Mice Lacking the Alpha9 Subunit of the Nicotinic Acetylcholine Receptor Exhibit Deficits in Frequency Difference Limens and Sound Localization. Front Cell Neurosci 11:167
Sturm, Joshua J; Zhang-Hooks, Ying-Xin; Roos, Hannah et al. (2017) Noise Trauma-Induced Behavioral Gap Detection Deficits Correlate with Reorganization of Excitatory and Inhibitory Local Circuits in the Inferior Colliculus and Are Prevented by Acoustic Enrichment. J Neurosci 37:6314-6330
Weisz, Catherine J C; Rubio, Maria E; Givens, Richard S et al. (2016) Excitation by Axon Terminal GABA Spillover in a Sound Localization Circuit. J Neurosci 36:911-25
Shelton, Micah A; Newman, Jason T; Gu, Hong et al. (2015) Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia. Biol Psychiatry 78:374-85
Sturm, Joshua; Nguyen, Tuan; Kandler, Karl (2014) Development of intrinsic connectivity in the central nucleus of the mouse inferior colliculus. J Neurosci 34:15032-46
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
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
Kandler, Karl; Nguyen, Tuan; Noh, Jihyun et al. (2013) An optical fiber-based uncaging system. Cold Spring Harb Protoc 2013:118-21
Nguyen, Tuan D; Wirblich, Christoph; Aizenman, Elias et al. (2012) Targeted single-neuron infection with rabies virus for transneuronal multisynaptic tracing. J Neurosci Methods 209:367-70
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

Showing the most recent 10 out of 30 publications