Biology subjects

Hübner, C. A.

Publications and source records attributed to Hübner, C. A..

3 recordsLinked to original sources

bioRxiv2021

The Cl- channel TMEM16A controls the generation of cochlear Ca2+ waves and promotes the refinement of auditory brainstem networks

Before hearing onset (postnatal day 12 in mice), inner hair cells (IHC) spontaneously fire action potentials thereby driving pre-sensory activity in the ascending auditory pathway. The rate of IHC action potential bursts is modulated by inner supporting cells (ISC) of Kollikers organ through the activity of the Ca2+ activated Cl- channel TMEM16A. Here we show that conditional deletion of Tmem16a in mice disrupts the generation of Ca2+ waves within Kollikers organ, reduces the burst firing activity and the frequency-selectivity of auditory brainstem neurons in the medial nucleus of the trapezoid body (MNTB), and also impairs the refinement of MNTB projections to the lateral superior olive (LSO). These results reveal the importance of the activity of Kollikers organ for the refinement of central auditory connectivity. In addition, our study suggests a mechanism for the generation of Ca2+ waves, which may also apply to other tissues expressing TMEM16A.

neuroscience↗

bioRxiv2021

Microglial NKCC1 shapes microglial phenotype, cerebral inflammatory responses and brain injury

The NKCC1 ion transporter contributes to the pathophysiology of common neurological disorders, but its function in microglia, the main inflammatory cells of the brain, has remained unclear to date. Therefore, we generated a novel transgenic mouse line in which microglial NKCC1 was deleted. We show that microglial NKCC1 shapes both baseline and reactive microglia morphology, process recruitment to the site of injury, and adaptation to osmotic stress in a cell-autonomous manner via regulating membrane potential and chloride fluxes. In addition, microglial NKCC1 deficiency results in increased expression of the D subunit of volume regulated anion channel (VRAC), NLRP3 inflammasome priming and production of interleukin-1{beta} (IL-1{beta}), rendering microglia prone to exaggerated inflammatory responses. In line with this, central (intracortical) administration of the NKCC1 blocker, bumetanide, potentiated intracortical lipopolysaccharide (LPS)-induced cytokine levels, whereas systemic bumetanide application decreased inflammation in the brain. Microglial NKCC1 KO animals exposed to experimental stroke showed significantly increased brain injury, inflammation, cerebral edema and worse neurological outcome. Thus, NKCC1 emerges as an important player in controlling microglial ion homeostasis and inflammatory responses through which microglia modulate brain injury. The contribution of microglia to central NKCC1 actions is likely to be relevant for common neurological disorders.

neuroscience↗

bioRxiv2020

Intraneuronal chloride accumulation via NKCC1 is not essential for hippocampal network development in vivo

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in-vitro excitatory GABA actions and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics and behavioral performance are subtle. Our data reveal a neural network function of depolarizing GABA in the hippocampus in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

neuroscience↗