Biology subjects

Lukashkina, V. A.

Publications and source records attributed to Lukashkina, V. A..

3 recordsLinked to original sources

bioRxiv2026

Connexin 30 mutation rescues high-frequency hearing, reduces gap junctional coupling and alters potassium currents in cochlear Deiters cells

The early-onset, high-frequency hearing loss phenotype of CD-1 mice is rescued by the A88V mutation of the connexin 30 gap-junctional protein, despite a reduced endocochlear potential (EP), which drives cochlear hair cell receptor potentials. The mutation enables organ of Corti (OoC) extracellular receptor potentials to be similar in size to those of sensitive-hearing CBA/J mice, presumably through increased OoC resistance, despite smaller intracellular outer hair cell (OHC) receptor potentials. Low-frequency hearing in CD-1Cx30A88V/A88V mice is impaired, compared with those of CBA/J and wild-type CD-1 mice. To investigate the cellular basis of OoC resistance increase and EP decrease, we made in situ electrophysiological measurements from Deiters cells (DCs) in the OoC of homozygous CD-1Cx30A88V/A88V mice. DCs contribute to the OHC cytoskeletal scaffold and cochlear K+ recycling, and are interconnected by syncytial junctions comprising connexins 30 and 26. Measurements from CD-1Cx30A88V/A88V mice were compared with those from wild-type CD-1 mice, with sensitive hearing below 12 kHz, and from the CBA/J strain. Syncytial junctional-coupling between DCs of CD-1Cx30A88V/A88V mice was weaker, input resistance greater, potassium current expression was modified, and voltage-sensitive activation was shifted to more negative values compared to those of CD-1 and CBA/J mice. Inactivating potassium currents dominate in DCs of CBA/J and CD-1Cx30A88V/A88V mice with excellent high-frequency hearing, and sustained currents dominate in DCs of CD-1 mice with early-onset hearing loss. These findings are discussed in relation to maintenance of OoC electrochemistry, rescue of early-onset hearing loss, impaired low-frequency hearing in CD-1Cx30A88V/A88V mice, and the basis of high-frequency hearing. KEY POINTS SUMMARYO_LIA88V mutation in gap-junctional protein Connexin 30 reshapes cochlear electrophysiology: The mutation increases organ of Corti resistance, raises Deiters cell input resistance, and weakens gap-junction coupling between supporting cells. Although it reduces endocochlear potential and low-frequency hearing, it preserves extracellular outer hair cell receptor potentials, rescuing high-frequency early-onset hearing loss in wild-type CD-1 mice. C_LIO_LIDeiters cell K+-conductances in mutants resemble those of the excellent-hearing CBA/J mice: Mutant CD-1 mice show potassium-channel properties nearly identical to CBA/J strain and distinct from wild-type CD-1 mice. These faster, more sensitive K+-conductances may enhance high-frequency hearing and support resistance to hearing loss. C_LIO_LIReduced gap-junction connectivity may protect against age-related hearing loss: Loss of heterotypic gap junctions and reduced supporting-cell connectivity may disrupt harmful feedback loops involved in noise-induced degeneration, explaining preserved high-frequency hearing in mutant CD-1 mice. C_LIO_LIOur findings provide bases for understanding mechanisms of high-frequency hearing and cochlear electrochemistry. C_LI

neuroscience↗

bioRxiv2023

Optogenetics reveals roles for supporting cells in force transmission to and from outer hair cells in the mouse cochlea

Cochlear outer hair cells (OHCs), acting as bidirectional cellular mechanoelectrical-transducers, generate, receive, and exchange forces with other major elements of the cochlear partition, including inner hair cells (IHCs). Force exchange is mediated via a supporting cell scaffold, including Deiters (DC) and outer pillar cells (OPC), to enable the sensitivity and exquisite frequency selectivity of the mammalian cochlea. We conditionally expressed a hyperpolarizing halorhodopsin (HOP), a light-gated inward chloride ion pump in DCs and OPCs. We measured extracellular receptor potentials (ERPs) and their DC component (ERPDC) from the Cortilymph (CL) of HOP expressing mice and compared the responses with similar potentials from littermates without HOP expression. Compound action potentials (CAP) were measured as an indication of IHC activity. HOP laser activation suppressed cochlear amplification through changing timing of its feedback, altered basilar membrane (BM) responses to tones at all measured levels and frequencies, and reduced IHC excitation. Our HOP activation results here complement previous channelrhodopsin activation studies in exploiting optogenetics to measure and understand the roles of DCs and OPCs in vivo in controlling the mechanical and electrical responses of OHCs to sound and their contribution to timed and directed electromechanical feedback to the mammalian cochlea. SIGNIFICANCE STATEMENTOuter hair cells provide electromechanical feedback to the organ of Corti, mediated via a cellular scaffold of Deiters and outer pillar cells, that enables the sensitivity and fine frequency tuning of the cochlea. The role of this scaffold was explored by expressing the halorhodopsin HOP in Deiters and pillar cells which, when illuminated, hyperpolarized them. HOP activation suppressed cochlear amplification through altering the timing of outer hair cell forces to the Organ of Corti, altered basilar membrane responses to tones, including those at levels and frequencies not subject to amplification, and reduced neural excitation. The findings implicated roles for supporting cells in mediating force transmission to and from outer hair cells along all axes of the organ of Corti.

neuroscience↗

bioRxiv2021

A gap-junction mutation in the mouse cochlea reveals cochlear amplification is driven by outer hair cell extracellular receptor potentials

Cochlear amplification, whereby cochlear responses to low-to-moderate sound levels are amplified and compressed to loud sounds, is attributed to outer hair cell (OHC) electromotility driven by voltage changes across the OHC basolateral membranes due to sound-induced receptor-current modulation. Cochlear operation at high acoustic frequencies is enigmatic because the OHC intracellular receptor potential (RP) is severely attenuated at these frequencies. Clues to understanding the voltage control of OHC electromotility at different frequencies was provided by measurements from CD-1 mice with an A88V mutation of the gap-junction (GJ) protein connexin 30 (Cx30), which with Cx26, form heterogeneous GJs between supporting cells in the organ of Corti (OoC) and stria vascularis. The A88V mutation results in a smaller GJ conductance which may explain why the resistance across the OoC in CD-1Cx30A88V/A88V mutants is higher compared with wild-type mice. The endocochlear potential, which drives the OHC receptor current and, consequently, the OHC RPs, is smaller in CD-1Cx30A88V/A88V mutants. Even so, their high-frequency hearing sensitivity equals that of wild-type mice. Preservation of high-frequency hearing correlates with similar amplitude of extracellular receptor potentials (ERPs), measured immediately adjacent to the OHCs. ERPs are generated through OHC receptor current flow across the OoC electrical resistance, which is larger in CD-1Cx30A88V/A88V than in wild-type mice. Thus, smaller OHC receptor currents flowing across a larger OoC resistance in CD-1Cx30A88V/A88V mice may explain why their ERP magnitudes are similar to wild-type mice. It is proposed that the ERPs, which are not subject to low-pass electrical filtering, drive high-frequency cochlear amplification. Significance StatementCochlear amplification, whereby responses to low-to-moderate sound levels are amplified and those to loud sounds are compressed, is attributed to outer hair cell (OHC) electromotility. Electromotility is driven by voltage changes across the OHC basolateral membranes due to modulation of receptor current flow during sound-induced sensory hair bundle displacement. Mechanisms of high-frequency cochlear amplification remain to be elucidated. A mutation of the gap-junction protein connexin 30 decreases OHC intracellular receptor potentials in CD-1 mice. Instead of decreasing auditory sensitivity, the mutation rescues high-frequency hearing by causing OHC extracellular receptor potentials to be similar in amplitude to those of sensitive wild-type mice. It is proposed extracellular, not intracellular, potentials drive high-frequency OHC motility and cochlear amplification at high acoustic frequencies.

neuroscience↗