Karl Kandler - US grants

DESCRIPTION (Adapted From The Applicant's Abstract): 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.

DESCRIPTION (provided by applicant): 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.

[unreadable] DESCRIPTION (provided by applicant): The first Gordon Research Conference (GRC) dedicated to the Auditory System will take place from June 29 - July 4, 2008 at Colby-Sawyer College, New London, New Hampshire. Deafness, auditory impairment, or tinnitus are major health issues affecting more than 10% of the population in the US. Impaired auditory processing is also associated with major developmental brain disabilities including developmental dyslexia, which is estimated to affect 10-15% of children in the US. The past decade has seen major progress in understanding the basic biological mechanisms of hearing and auditory system plasticity, in determining the genetic basis of deafness in humans, and in characterizing the deficits in auditory processing that are associated with developmental dyslexia and other developmental and communicative disabilities. One of the major challenges now lies in translating the detailed knowledge the field has gained from animal and human studies into effective treatment strategies. The major goal of the Auditory System GRC is to bring together world-leading auditory scientists and junior investigators to present and discuss current key issues in the field of auditory science. The Auditory System GRC fills the need for a relatively small-size and interdisciplinary meeting that will provide a forum for intense cross-disciplinary discussion in an informal setting. This will encourage innovative cross-disciplinary collaborations, help to identify critical key issues that need to be addressed in future research, and facilitate the formulation of new conceptual frameworks on both a basic science as well as on a translational level. To strongly encourage the participation of junior scientists, the Auditory System GRC will be accompanied by a Gordon-Kenan Graduate/Postdoc Research Seminar (GKGRS) on auditory neuroscience. The Gordon Research Conference (GRC) on the Auditory System will bring together world-leading auditory scientists and students to provide an interdisciplinary forum that will foster the translation of knowledge that the auditory field has gained from animal studies into effective treatment strategies for humans. [unreadable] [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): This application requests funds to continue a training program in auditory and vestibular neuroscience at the University of Pittsburgh. Resources to support two predoctoral and two postdoctoral trainees per year are requested. While considerable progress has been made in identifying the genetic and molecular bases of inner ear deficits, the biological bases of centrally-generated hearing and balance disorders, which are increasingly recognized as major contributors to auditory and vestibular dysfunction, are still poorly understood. The proposed program is intended to generate auditory and vestibular scientists who can address these problems, through training in basic neuroscience and the clinical aspects of hearing and balance disorders. A group of 15 preceptors who are committed to auditory and vestibular neuroscience research and to recruit and educate outstanding pre- and postdoctoral fellows will comprise the training faculty. The research methodology employed by the preceptors ranges from cellular and molecular to developmental to systems and cognition using a variety of model systems, ensuring that trainees use are exposed to the breadth and variety of technical and conceptual approaches that define modern research in the field. In addition to conducting research, trainees attend monthly research seminars, and participate in a series of professional development workshops that provide explicit training in such survival skills as written and oral communication, obtaining jobs and grants, teaching, and managing a research lab. All trainees must submit a fellowship application as part of the program, the writing of which will be facilitated by periodic meetings with a local committee that provides advice and guidance, as well as utilizing grant-writing workshops provided by the office of academic career development. Training in the responsible scientific conduct is an integral part of the professional development workshops, the core curriculum, and laboratory training. A solid structure is in place to mentor the trainees and monitor their progress through the program.