Papers by Marlies Knipper
Development, 1998
All cranial nerves, as well as the VIIIth nerve which invades the cochlea, have a proximal end in... more All cranial nerves, as well as the VIIIth nerve which invades the cochlea, have a proximal end in which myelin is formed by Schwann cells and a distal end which is surrounded by oligodendrocytes. The question which arises in this context is whether peripheral and central parts of these nerves myelinate simultaneously or subsequently and whether the myelination of either of the parts occurs simultaneously at the onset of the cochlea function and under the control of neuronal activity. In the present paper, we examined the relative time course of the myelinogenesis of the distal part of the VIIIth nerve by analyzing the expression of peripheral protein P0, proteolipid protein and myelin basic protein. To our surprise, we observed that the expression of myelin markers in the peripheral and central part of the intradural part of the VIIIth nerve started simultaneously, from postnatal day 2 onwards, long before the onset of cochlea function. The expression rapidly achieved saturation lev...
Frontiers in Neural Circuits
Neuronal hyperexcitability in the central auditory pathway linked to reduced inhibitory activity ... more Neuronal hyperexcitability in the central auditory pathway linked to reduced inhibitory activity is associated with numerous forms of hearing loss, including noise damage, age-dependent hearing loss, and deafness, as well as tinnitus or auditory processing deficits in autism spectrum disorder (ASD). In most cases, the reduced central inhibitory activity and the accompanying hyperexcitability are interpreted as an active compensatory response to the absence of synaptic activity, linked to increased central neural gain control (increased output activity relative to reduced input). We here suggest that hyperexcitability also could be related to an immaturity or impairment of tonic inhibitory strength that typically develops in an activity-dependent process in the ascending auditory pathway with auditory experience. In these cases, high-SR auditory nerve fibers, which are critical for the shortest latencies and lowest sound thresholds, may have either not matured (possibly in congenital...
Thyroid hormone deficiency before the onset of hearing causes irreversible damage to peripheral a... more Thyroid hormone deficiency before the onset of hearing causes irreversible damage to peripheral and central auditory systems. J. Neurophysiol. 83: 3101-3112, 2000. Both a genetic or acquired neonatal thyroid hormone (TH) deficiency may result in a profound mental disability that is often accompanied by deafness. The existence of various TH-sensitive periods during inner ear development and general success of delayed, corrective TH treatment was investigated by treating pregnant and lactating rats with the goitrogen methimazole (MMI). We observed that for the establishment of normal hearing ability, maternal TH, before fetal thyroid gland function on estrus days 17-18, is obviously not required. Within a crucial time between the onset of fetal thyroid gland function and the onset of hearing at postnatal day 12 (P12), any postponement in the rise of TH-plasma levels, as can be brought about by treating lactating mothers with MMI, leads to permanent hearing defects of the adult offspring. The severity of hearing defects that were measured in 3-to 9-mo-old offspring could be increased with each additional day of TH deficiency during this critical period. Unexpectedly, the active cochlear process, assayed by distortion product otoacoustic emissions (DPOAE) measurements, and speed of auditory brain stem responses, which both until now were not thought to be controlled by TH, proved to be TH-dependent processes that were damaged by a delay of TH supply within this critical time. In contrast, no significant differences in the gross morphology and innervation of the organ of Corti or myelin gene expression in the auditory system, detected as myelin basic protein (MBP) and proteolipid protein (PLP) mRNA using Northern blot approach, were observed when TH supply was delayed for few days. These classical TH-dependent processes, however, were damaged when TH supply was delayed for several weeks. These surprising results may suggest the existence of different TH-dependent processes in the auditory system: those that respond to corrective TH supply (e.g., innervation and morphogenesis of the organ of Corti) and those that do not, but require T3 activity during a very tight time window (e.g., active cochlear process, central processes).
Frontiers in Aging Neuroscience
In the inner ear, cyclic guanosine monophosphate (cGMP) signaling has been described as facilitat... more In the inner ear, cyclic guanosine monophosphate (cGMP) signaling has been described as facilitating otoprotection, which was previously observed through elevated cGMP levels achieved by phosphodiesterase 5 inhibition. However, to date, the upstream guanylyl cyclase (GC) subtype eliciting cGMP production is unknown. Here, we show that mice with a genetic disruption of the gene encoding the cGMP generator GC-A, the receptor for atrial and B-type natriuretic peptides, display a greater vulnerability of hair cells to hidden hearing loss and noise-and age-dependent hearing loss. This vulnerability was associated with GC-A expression in spiral ganglia and outer hair cells (OHCs) but not in inner hair cells (IHCs). GC-A knockout mice exhibited elevated hearing thresholds, most pronounced for the detection of high-frequency tones. Deficits in OHC input-output functions in high-frequency regions were already present in young GC-Adeficient mice, with no signs of an accelerated progression of age-related hearing loss or higher vulnerability to acoustic trauma. OHCs in these frequency regions in young GC-A knockout mice exhibited diminished levels of KCNQ4 expression, which is the dominant K + channel in OHCs, and decreased activation of poly (ADP-ribose) polymerase-1, an enzyme involved in DNA repair. Further, GC-A knockout mice had IHC synapse impairments and reduced amplitudes of auditory brainstem responses that progressed with age and with acoustic trauma, in contrast to OHCs, when compared to GC-A wildtype littermates. We conclude that GC-A/cGMP-dependent signaling pathways have otoprotective functions and GC-A gene disruption differentially contributes to hair-cell damage in a healthy, aged, or injured system. Thus, augmentation of natriuretic peptide GC-A signaling likely has potential to overcome hidden and noise-induced hearing loss, as well as presbycusis.
Brain-derived neurotrophic factor (BDNF) is a key neurotrophin whose expression is altered in res... more Brain-derived neurotrophic factor (BDNF) is a key neurotrophin whose expression is altered in response to neurological activity, influencing both short-and long-term synaptic changes. The BDNF gene consists of eight upstream exons (I-VII), each of which has a distinct promoter, and can be independently spliced to the ninth coding exon (IX). We recently showed that the expression of BDNF exon IV in the cochlea is altered following exposure to salicylate, an ototoxic drug that in high doses is able to induce hearing loss and tinnitus. These changes were a crucial trigger for plasticity changes in the central auditory system. BDNF exon IV expression is regulated via interaction between calcium response elements CaRE1, CaRE2 and CaRE3/Cre (CaREs) that are bound by the transcription factors CaRF1, USF1/2 and CREB, respectively. To determine if the salicylate induced changes in cochlear BDNF exon IV expression include a differential use of the CaRE binding proteins, we studied the level of the corresponding bindingproteins in the spiral ganglion neurons prior to and following systemic application of concentrated salicylate using in situ hybridization and RT-PCR. BDNF exon IV and CaRF1 expression were upregulated following application of salicylate, while USF1/2 and CREB mRNA expression remained unaffected. The changes in BDNF exon IV and CaRF1 expression were also dose-dependent. The data show Ca 2+ and CaRF1 as messengers of trauma (salicylate)induced altered BDNF levels in the cochlea. Furthermore, they also provide the first evidence that a differential regulation of BDNF transcription factors might participate in BDNF-mediated plasticity changes.
Hearing, Balance and Communication, 2020
Tinnitus is associated with damages in the peripheral auditory system and changes in signal proce... more Tinnitus is associated with damages in the peripheral auditory system and changes in signal processing along the ascending auditory pathway. Furthermore, within the last years it became evident that beside nuclei of the auditory system associated brain areas like the limbic system are involved in the chronic manifestation of tinnitus. To better understand the processes that take place during the development of tinnitus, diagnostic tools are required that allow an analysis beyond the auditory system including associated brain areas. In this review, we report results from corporate investigations of the auditory periphery (hearing function), signal transmission along the ascending auditory pathway (ABR wave analysis) and central nervous activity (MEMRI).
Journal of the Association for Research in Otolaryngology
A curative therapy for tinnitus currently does not exist. One may actually exist but cannot curre... more A curative therapy for tinnitus currently does not exist. One may actually exist but cannot currently be causally linked to tinnitus due to the lack of consistency of concepts about the neural correlate of tinnitus. Depending on predictions, these concepts would require either a suppression or enhancement of brain activity or an increase in inhibition or disinhibition. Although procedures with a potential to silence tinnitus may exist, the lack of rationale for their curative success hampers an optimization of therapeutic protocols. We discuss here six candidate contributors to tinnitus that have been suggested by a variety of scientific experts in the field and that were addressed in a virtual panel discussion at the ARO round table in February 2021. In this discussion, several potential tinnitus contributors were considered: (i) inhibitory circuits, (ii) attention, (iii) stress, (iv) unidentified sub-entities, (v) maladaptive information transmission, and (vi) minor cochlear deaff...
Clinical and Translational Medicine
To the Editor: We recently observed that tinnitus is associated with reduced auditory input that ... more To the Editor: We recently observed that tinnitus is associated with reduced auditory input that fails to increase neural gain due to diminished stimulus-evoked responses.1–3 This was in contrast to views that suggested a homeostatic increase in neural gain to generate central hyper-excitability leading to tinnitus.4 A curative therapy for tinnitus currently does not exist. Its progress is mostly impeded by the existing controversial views about the neural correlate of tinnitus that, depending on predictions, either would require the suppression or the enhancement of brain activity. We hypothesized that different neural correlates of tinnitus, whether with or without the co-occurrence of hyperacusis, contributed to this dilemma. To test this hypothesis, we recruited 43 controls and 50 audiologically examined tinnitus patients with andwithout a co-occurrence of hyperacusis (Tables S1 and S2) and performed brainstemaudiometry (ABR) and functional imaging of brain activity (fMRI). Among the group of 50 tinnitus patients, 20 could be identified with the co-occurrence of hyperacusis (T+H group) from the HKI hyperacusis questionnaire (Figure 1A).5 The overall score of the Goebel and Hiller Score (G-H-S) tinnitus questionnaire6 was significantly higher for the T+H group than the tinnitus-only patients (T group) (Figure 1B, p< .001***) for nearly all subscores (Figure S1, p < .002***). In the T+H group (Figure 1D) but not the T group (Figure 1C), auditory perceptional difficulty became worse for patients with self-rated tinnitus loudness ≤15 dB HL (Figure 1E, Figure S2). The T and T+H group differences in annoyance and distress were not linked to differences in hearing sensitivity (Figure S3A– C, p > .5), since pure tone audiometry (PTA) thresholds (Supporting Material1) were not different between groups. In contrast, supra-threshold ABR by brainstemevoked response audiometry (BERA)1,2 revealed group differences: In T group, significantly reduced ABR wave V amplitude together with significantly prolonged interpeak latency (IPL) I–V (Figure 1F,H,J; Table S3) and reduced
Pflügers Archiv - European Journal of Physiology
Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly and constitu... more Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly and constitutes the third highest risk factor for dementia. Lifetime noise exposure, genetic predispositions for degeneration, and metabolic stress are assumed to be the major causes of ARHL. Both noise-induced and hereditary progressive hearing have been linked to decreased cell surface expression and impaired conductance of the potassium ion channel KV7.4 (KCNQ4) in outer hair cells, inspiring future therapies to maintain or prevent the decline of potassium ion channel surface expression to reduce ARHL. In concert with KV7.4 in outer hair cells, KV7.1 (KCNQ1) in the stria vascularis, calcium-activated potassium channels BK (KCNMA1) and SK2 (KCNN2) in hair cells and efferent fiber synapses, and KV3.1 (KCNC1) in the spiral ganglia and ascending auditory circuits share an upregulated expression or subcellular targeting during final differentiation at hearing onset. They also share a distinctive fragi...
Frontiers in Neurology
Although tinnitus represents a major global burden, no causal therapy has yet been established. O... more Although tinnitus represents a major global burden, no causal therapy has yet been established. Ongoing controversies about the neuronal pathophysiology of tinnitus hamper efforts in developing advanced therapies. Hypothesizing that the unnoticed co-occurrence of hyperacusis and differences in the duration of tinnitus may possibly differentially influence the neural correlate of tinnitus, we analyzed 33 tinnitus patients without (T-group) and 20 tinnitus patients with hyperacusis (TH-group). We found crucial differences between the T-group and the TH-group in the increase of annoyance, complaints, tinnitus loudness, and central neural gain as a function of tinnitus duration. Hearing thresholds did not differ between T-group and TH-group. In the TH-group, the tinnitus complaints (total tinnitus score) were significantly greater from early on and the tinnitus intensity distinctly increased over time from ca. 12 to 17 dB when tinnitus persisted more than 5 years, while annoyance respon...
Frontiers in Molecular Neuroscience
Numerous studies indicate that deficits in the proper integration or migration of specific GABAer... more Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants ofBdnfPax2KOs causes severe cognitive disabilities. InBdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here:Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elev...
British Journal of Pharmacology
cGMP is generated by the cGMP-forming guanylyl cyclases (GC), the intracellular nitric oxide (NO)... more cGMP is generated by the cGMP-forming guanylyl cyclases (GC), the intracellular nitric oxide (NO)-sensitive (soluble) guanylyl cyclase (sGC), and transmembrane GC (e.g. GC-A and GC-B). Summarizing the particular role of cGMP signalling for hearing, we show that GC generally do not interfere significantly with basic hearing function but rather sustain a healthy state for proper temporal coding, fast discrimination, and adjustments during injury. sGC is critical for the integrity of the first synapse in the ascending auditory pathway, the inner hair cell (IHC) synapse. GC-A promotes hair cell stability under stressful conditions such as acoustic trauma or ageing. GC-B plays a role in the development of efferent feed-back and gain control. Regarding the crucial role hearing has for language development, speech discrimination, and cognitive brain functions, differential pharmaceutical targeting of GC offers therapeutic promise for the restoration of hearing.
Brain Sciences
Age-related decoupling of auditory nerve fibers from hair cells (cochlear synaptopathy) has been ... more Age-related decoupling of auditory nerve fibers from hair cells (cochlear synaptopathy) has been linked to temporal processing deficits and impaired speech recognition performance. The link between both is elusive. We have previously demonstrated that cochlear synaptopathy, if centrally compensated through enhanced input/output function (neural gain), can prevent age-dependent temporal discrimination loss. It was also found that central neural gain after acoustic trauma was linked to hippocampal long-term potentiation (LTP) and upregulation of brain-derived neurotrophic factor (BDNF). Using middle-aged and old BDNF-live-exon-visualization (BLEV) reporter mice we analyzed the specific recruitment of LTP and the activity-dependent usage of Bdnf exon-IV and -VI promoters relative to cochlear synaptopathy and central (temporal) processing. For both groups, specimens with higher or lower ability to centrally compensate diminished auditory nerve activity were found. Strikingly, low compen...
Comparative Biochemistry and Physiology Part C: Comparative Pharmacology
A collection of neurotoxins, known to affect the sodium permeability of neuronal membranes, was a... more A collection of neurotoxins, known to affect the sodium permeability of neuronal membranes, was analysed concerning their ability to perturb the high-affinity choline uptake system in membrane vesicles prepared from Iocust synaptosomes. 2. The initial transport rate as well as the overall capacity of choline accumulation was significantly reduced by toxins which affect Na+-flux and Na'-gradients (veratridine, scorpion toxin, sea anemone toxin). 3. This inhibitory effect was prevented by the channel blocker tetrodotoxin.
HNO
ZusammenfassungDemografischer Wandel und verändertes Freizeitverhalten lassen in den nächsten 20–... more ZusammenfassungDemografischer Wandel und verändertes Freizeitverhalten lassen in den nächsten 20–30 Jahren eine rapide Zunahme von Hörstörungen erwarten. Damit steigt das Risiko, an altersbedingtem Sprachdiskriminationsverlust, Tinnitus, Hyperakusis oder, wie neueste Studien postulieren, an Demenz zu erkranken. Es verdichten sich Hinweise darauf, dass bei Mensch und Tier der Verlust spezifischer Hörfasern an verschiedenen Hörstörungen beteiligt ist. Dieser Hörfaserverlust kann durch cochleäre Synaptopathie oder Deafferenzierung verursacht werden und führt nicht zwangsläufig zu klinisch messbaren Hörschwellenabweichungen. Tierexperimentell wurde belegt, dass eine verminderte Hörnervaktivität nach akustischem Trauma oder durch Alter zentral über eine disproportional erhöhte und schnellere akustisch evozierte Stammhirnantwort kompensiert werden kann. Die Analyse der überschwelligen Amplituden von auditorisch evozierten Hirnstammpotenzialen und deren Latenz in Kombination mit nichtinvasiven bildgebenden Techniken wie die Magnetresonanztomographie können helfen die zentrale Kompensationsfähigkeit von Probanden zu identifizieren und definierten Hördefiziten zuzuordnen.AbstractDue to demographic change and altered recreational behavior, a rapid increase in hearing deficits is expected in the next 20–30 years. Consequently, the risk of age-related loss of speech discrimination, tinnitus, hyperacusis, or—as recently shown—dementia, will also increase. There are increasing indications that the loss of specific hearing fibers in humans and animals is involved in various hearing disorders. This fiber loss can be caused by cochlear synaptopathy or deafferentation and does not necessarily lead to clinically measurable threshold changes. Animal experiments have shown that reduced auditory nerve activity due to acoustic trauma or aging can be centrally compensated by disproportionately elevated and faster auditory brainstem responses (ABR). The analysis of the suprathreshold amplitudes of auditory evoked brain stem potentials and their latency in combination with non-invasive imaging techniques such as magnetic resonance imaging can help to identify the central compensatory ability of subjects and to assign defined hearing deficits.
BMC Pharmacology and Toxicology
Frontiers in Molecular Neuroscience
Activity-dependent BDNF (brain-derived neurotrophic factor) expression is hypothesized to be a cu... more Activity-dependent BDNF (brain-derived neurotrophic factor) expression is hypothesized to be a cue for the context-specificity of memory formation. So far, activity-dependent BDNF cannot be explicitly monitored independently of basal BDNF levels. We used the BLEV (BDNF-live-exon-visualization) reporter mouse to specifically detect activity-dependent usage of Bdnf exon-IV and-VI promoters through bi-cistronic co-expression of CFP and YFP, respectively. Enriching acoustic stimuli led to improved peripheral and central auditory brainstem responses, increased Schaffer collateral LTP, and enhanced performance in the Morris water maze. Within the brainstem, neuronal activity was increased and accompanied by a trend for higher expression levels of Bdnf exon-IV-CFP and exon-VI-YFP transcripts. In the hippocampus BDNF transcripts were clearly increased parallel to changes in parvalbumin expression and were localized to specific neurons and capillaries. Severe acoustic trauma, in contrast, elevated neither Bdnf transcript levels, nor auditory responses, parvalbumin or LTP. Together, this suggests that critical sensory input is essential for recruitment of activity-dependent auditory-specific BDNF expression that may shape network adaptation.
Forschung heute – Zukunft morgen
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2018
From invertebrates to mammals, Gαi proteins act together with their common binding partner Gpsm2 ... more From invertebrates to mammals, Gαi proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gαi3-deficiency in pre-hearing murine cochleae pointed to a role of Gαi3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary ("hair") bundle, a requirement for the progression of mature hearing. We found that the lack of Gαi3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear. Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Gαi proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with fu...
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Papers by Marlies Knipper