Vesicular glutamatergic transmission in noise-induced loss and repair of cochlear ribbon synapses

Noise-induced excitotoxicity is thought to depend on glutamate. However, the excitotoxic mechanisms are unknown, and the necessity of glutamate for synapse loss or regeneration is unclear. Despite absence of glutamatergic transmission from cochlear inner hair cells in mice lacking the vesicular glutamate transporter-3

Author's personal copy Anti-epileptic drugs delay age-related loss of spiral ganglion neurons via T-type calcium channel

a b s t r a c t Loss of spiral ganglion neurons is a major cause of age-related hearing loss (presbycusis). Despite being the third most prevalent condition afflicting elderly persons, there are no known medications to prevent presbycusis. Because calcium signaling has long been implicated in age-related neuronal death, we investigated T-type calcium channels. This family is comprised of three members (Ca v 3.1, Ca v 3.2, and Ca v 3.3), based on their respective main pore-forming alpha subunits: a1G, a1H, and a1I. In the present study, we report a significant delay of age-related loss of cochlear function and preservation of spiral ganglion neurons in a1H null and heterozygous mice, clearly demonstrating an important role for Ca v 3.2 in age-related neuronal loss. Furthermore, we show that anticonvulsant drugs from a family of T-type calcium channel blockers can significantly preserve spiral ganglion neurons during aging. To our knowledge, this is the first report of drugs capable of diminishing age-related loss of spiral ganglion neurons

LRRC52 regulates BK channel function and localization in mouse cochlear inner hair cells

The perception of sound relies on sensory hair cells in the cochlea that convert the mechanical energy of sound into release of glutamate onto postsynaptic auditory nerve fibers. The hair cell receptor potential regulates the strength of synaptic transmission and is shaped by a variety of voltage-dependent conductances. Among these conductances, the Ca2+- and voltage-activated large conductance Ca2+-activated K+ channel (BK) current is prominent, and in mammalian inner hair cells (IHCs) displays unusual properties. First, BK currents activate at unprecedentedly negative membrane potentials (−60 mV) even in the absence of intracellular Ca2+ elevations. Second, BK channels are positioned in clusters away from the voltage-dependent Ca2+ channels that mediate glutamate release from IHCs. Here, we test the contributions of two recently identified leucine-rich-repeat–containing (LRRC) regulatory γ subunits, LRRC26 and LRRC52, to BK channel function and localization in mouse IHCs. Whereas BK currents and channel localization were unaltered in IHCs from Lrrc26 knockout (KO) mice, BK current activation was shifted more than +200 mV in IHCs from Lrrc52 KO mice. Furthermore, the absence of LRRC52 disrupted BK channel localization in the IHCs. Given that heterologous coexpression of LRRC52 with BK α subunits shifts BK current gating about −90 mV, to account for the profound change in BK activation range caused by removal of LRRC52, we suggest that additional factors may help define the IHC BK gating range. LRRC52, through stabilization of a macromolecular complex, may help retain some other components essential both for activation of BK currents at negative membrane potentials and for appropriate BK channel positioning.Fil: Lingle, Christopher J.. Washington University in St. Louis; Estados UnidosFil: Martinez Espinosa, Pedro L.. Washington University in St. Louis; Estados UnidosFil: Yang Hood, Aizhen. Washington University in St. Louis; Estados UnidosFil: Boero, Luis Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Payne, Shelby. Washington University in St. Louis; Estados UnidosFil: Persic, Dora. University of Groningen; Países BajosFil: V-Ghaffari, Babak. Washington University in St. Louis; Estados UnidosFil: Xiao, Maolei. Washington University in St. Louis; Estados UnidosFil: Zhou, Yu. Washington University in St. Louis; Estados UnidosFil: Xia, Xiao Ming. Washington University in St. Louis; Estados UnidosFil: Pyott, Sonja J.. University of Groningen; Países BajosFil: Rutherford, Mark A.. Washington University in St. Louis; Estados Unido