Biology subjects

Dionisio, L.

Publications and source records attributed to Dionisio, L..

4 recordsLinked to original sources

bioRxiv2026

Impaired development of the medial olivocochlear system in a KCNQ4-deficient mouse model.

The medial olivocochlear (MOC) efferent system modulates outer hair cell (OHC) excitability and protects cochlea from overstimulation. Cholinergic activation of 910 nicotinic acetylcholine receptors (nAChRs) triggers Ca{superscript 2} influx, activating BK and SK2 Ca{superscript 2}-dependent K channels, and K extrusion through KCNQ4 to restore membrane potential. KCNQ4-loss causes chronic depolarization, OHC dysfunction, and hearing loss. Here, we investigated how KCNQ4 deficiency affects cochlear efferent synapse development and organization. Using confocal immunofluorescence, we analyzed efferent innervation in the organ of Corti of Kcnq4-/- (KO) and Kcnq4+/+(WT) mice at 2, 3, 4, and 10 postnatal weeks (W). At 2 W, efferent terminals were similarly distributed between basal and lateral OHC membrane domains in both genotypes. During maturation, WT mice exhibited complete relocation of MOC terminals to the basal domain, whereas KO mice showed delayed maturation, with some terminals laterally displaced up to 10 W. KCNQ4 absence was associated with reduced number and volume of efferent boutons on OHCs. Milder morphometric alterations were observed in efferent boutons within the inner hair cell region. At the molecular level, qPCR revealed downregulation of 10 nAChR subunit, BK, and SK2 transcripts in KO at 4 W, with recovery to 10 W. Despite this recovery, BK protein showed reduced expression, mislocalization, and disorganized synaptic plaques in OHCs. KO also displayed age-dependent upregulation of the calcium-binding proteins calbindin and calretinin, suggesting compensatory responses to altered Ca+{superscript 2} homeostasis. Together, these findings demonstrate that KCNQ4 is essential for OHC repolarization, maturation and maintenance of cochlear efferent synapses. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/700803v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@134e2caorg.highwire.dtl.DTLVardef@1155f45org.highwire.dtl.DTLVardef@21b4ccorg.highwire.dtl.DTLVardef@e4ee62_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Insights into early cochlear damage induced by potassium channel deficiency

Hearing loss (HL) is the most common sensory disorder, caused by genetic mutations and acquired factors like presbycusis and noise exposure. A critical factor in HL development is the dysfunction of potassium (K+) channels, essential for sensory cell function in the organ of Corti (OC). Inner and outer hair cells (IHCs and OHCs) convert sound into electrical signals, while supporting cells (SCs) maintain ionic and structural balance. KCNQ4 channels, located in the basal membrane of OHCs, regulate K+ efflux. Mutations in KCNQ4 are linked to progressive HL (DFNA2), noise-induced hearing loss, and presbycusis, leading to K+ accumulation, cellular stress, and OHC death. Gene editing or pharmacological activation of KCNQ4 has shown potential in partially preventing HL in mouse models. In this study, we demonstrate KCNQ4 deletion disrupts the localization of key proteins like prestin and BK channels, alters OHC organization, and induces apoptosis in sensory and SC. Spiral ganglion neurons (SGNs) also degenerate over time. Despite these structural changes, noise exposure does not exacerbate OHC damage in our KCNQ4-deficient model. This highlights KCNQ4s role in maintaining ion homeostasis and cochlear function, as its absence triggers widespread dysfunction in the OC. The present study demonstrates that disruptions in a single cell type can have a cascade effect on overall cochlear health. Understanding the molecular and cellular consequences of KCNQ4 mutations is crucial for developing targeted therapies to mitigate progressive HL caused by genetic and environmental factors. HighlightsO_LIHearing function is altered in KCNQ4 KO animals from young ages. C_LIO_LIInner hair cells show structural alterations before their death. C_LIO_LIKCNQ4 absence impairs membrane localization of key functional proteins. C_LIO_LIHair cell and neuron loss is mediated by apoptosis. C_LIO_LISupporting cells and satellite cells also contribute to tissue degeneration in KCNQ4 KO animals C_LIO_LINoise exposure does not exacerbate hair cell damage in KCNQ4-KO mice. C_LI

neuroscience↗

bioRxiv2020

The KCNQ4-mediated M-current regulates the circadian rhythm in mesopontine cholinergic neurons

The M-current is a voltage gated potassium current inhibited by muscarinic activation and affected by several other G-protein coupled receptors. Its channels are formed by KCNQ subunits, from which KCNQ4 is restricted to certain brainstem structures. We sought evidence for the function of the M-current in the pedunculopontine nucleus (PPN) and the contribution of KCNQ4 subunits to the M-current and aimed to find its functional significance in the PPN. We found that cholinergic inputs of the PPN can effectively inhibit M-current. This current is capable of synchronizing neighboring neurons and inhibition of the M-current decreases neuronal synchronization. We showed that only a subpopulation of cholinergic neurons has KCNQ4-dependent M-current. The KCNQ4 subunit expression potentially regulates the presence of other KCNQ subunits. Deletion of KCNQ4 leads to alterations in adaptation of activity to light-darkness cycles, thus representing the potential role of KCNQ4 in regulation of sleep-wakefulness cycles. The presence of this protein restricted to certain brainstem nuclei raises the possibility that it might be a potential target for selective therapeutic interventions affecting the reticular activating system.

neuroscience↗

bioRxiv2018

Time-course Pattern of Cell Degeneration in a Mouse with Cochlear Hair Cell Impaired Potassium Outflow

HIGHLIGHTSO_LIKCNQ4 knock-out mouse shows hair cells and spiral ganglion neuron degeneration.\nC_LIO_LIInner hair cells and spiral ganglion neuron loss begin 30 weeks later than outer hair cells in Kcnq4-/- mice.\nC_LIO_LIInner hair cell loss kinetic is faster than that of outer hair cells in cochlear basal turn in Kcnq4-/-.\nC_LIO_LIOuter hair cells from Kcnq4-/- mice degenerate slower in apical than in basal turn.\nC_LIO_LIKcnq4 knock-out allele expressed in C3H/HeJ strain reproduces the two phases of DFNA2 hearing loss.\nC_LI\n\nGRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC=\"FIGDIR/small/469676_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (31K):\norg.highwire.dtl.DTLVardef@1bdff20org.highwire.dtl.DTLVardef@b8cc51org.highwire.dtl.DTLVardef@6deeb9org.highwire.dtl.DTLVardef@153f381_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗