The goal of this proposal is to understand synaptic transmission at the vestibular type I hair cell/calyx synapse. Three classes of morphological afferents have been described in the amniote crista and utricle. Calyx units contact type I hair cells (HCI) exclusively, bouton units contact type II hair cells only & dimorphic units receive innervation from both bouton & calyx fibers (Goldberg, 2000). The physiological response dynamics of these three classes of fibers vary, with calyx units having the most irregular firing pattern & the lowest gains to rotational stimuli (Baird et al. 1988; Lysakowski et al. 1995). The reasons for these variations are unclear, but are hypothesized to include differences in hair cell mechano-electrical transduction (MET) properties & differences in the biophysical membrane properties of primary vestibular afferents. We will study HCI & associated calyx afferents to determine how firing patterns in this unique terminal are shaped by both pre- & post-synaptic mechanisms.
In Aim 1, patch clamp techniques will be used to study ionic conductances & transmitter release in a newly developed preparation of calyx terminals isolated together with HCI from gerbil vestibular organs (Rennie & Streeter, 2006). Excitatory postsynaptic currents (EPSCs) resulting from hair cell transmitter release will be recorded from calyx terminals under a variety of conditions.
In Aim 2 we will record MET currents & receptor potentials from HCI during displacement of the hair bundle with a stiff probe in a wholemount utricle preparation.
In Aim 3, mathematical modeling techniques will be employed to simulate HCI & calyx responses to glutamate. The passive electrical properties of the calyx & attached axon will be simulated with a segmented computational model in the NEURON programming environment. Na+, Ca2+ and K+ channels will be modeled with Hodgkin-Huxley style rate constants using the experimental data obtained in Aims 1& 2. A genetic algorithm wiil be used to optimize the kinetic parameters for the activation & inactivation of ionic conductances. Dizziness is one of the most common medical complaints. Understanding the basic cellular mechanisms of balance sensation is essential to lay the groundwork for identifying causes & cures for this debilitating condition. The combination of experimental & modeling approaches will elucidate how sensory information is transformed by HC1 & converted into a neural code by their afferents. ? ? ?
| Mann, Scott E; Johnson, Matthew; Meredith, Frances L et al. (2013) Inhibition of K+ currents in type I vestibular hair cells by gentamicin and neomycin. Audiol Neurootol 18:317-26 |
| Meredith, Frances L; Benke, Tim A; Rennie, Katherine J (2012) Hyperpolarization-activated current (I(h)) in vestibular calyx terminals: characterization and role in shaping postsynaptic events. J Assoc Res Otolaryngol 13:745-58 |
| Meredith, Frances L; Li, Gang Q; Rennie, Katherine J (2011) Postnatal expression of an apamin-sensitive k(ca) current in vestibular calyx terminals. J Membr Biol 244:81-91 |
| Dhawan, Ritu; Mann, Scott E; Meredith, Frances L et al. (2010) K+ currents in isolated vestibular afferent calyx terminals. J Assoc Res Otolaryngol 11:463-76 |
| Li, Gang Q; Meredith, Frances L; Rennie, Katherine J (2010) Development of K(+) and Na(+) conductances in rodent postnatal semicircular canal type I hair cells. Am J Physiol Regul Integr Comp Physiol 298:R351-8 |
