TY  - JOUR
A1  - Liu, Sheng
A1  - Bonalume, Veronica
A1  - Gao, Qi
A1  - Chen, Jeremy Tsung-Chieh
A1  - Rohr, Karl
A1  - Hu, Jing
A1  - Carr, Richard
T1  - Pre-synaptic GABA\(_A\) in NaV1.8\(^+\) primary afferents is required for the development of punctate but not dynamic mechanical allodynia following CFA inflammation
JF  - Cells
N2  - Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABA\(_A\) in NaV1.8-positive sensory neurons (Scn10a\(^{Cre}\);Gabrb3\(^{fl/fl}\)) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABA\(_A\). Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of c-fos mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABA\(_A\) and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I–V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund’s adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8\(^+\) afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABA\(_A\) in NaV1.8\(^+\) nociceptors constitutes an “open gate” pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits.
KW  - GABA\(_A\)
KW  - presynaptic inhibition
KW  - NaV1.8
KW  - spinal dorsal horn
KW  - punctate mechanical allodynia
KW  - c-fos
KW  - electrical excitability
KW  - activity-dependent slowing
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286081
SN  - 2073-4409
VL  - 11
IS  - 15
ER  - 
TY  - JOUR
A1  - Chumak, Tetyana
A1  - Rüttiger, Lukas
A1  - Lee, Sze Chim
A1  - Campanelli, Dario
A1  - Zuccotti, Annalisa
A1  - Singer, Wibke
A1  - Popelář, Jiří
A1  - Gutsche, Katja
A1  - Geisler, Hyun-Soon
A1  - Schraven, Sebastian Philipp
A1  - Jaumann, Mirko
A1  - Panford-Walsh, Rama
A1  - Hu, Jing
A1  - Schimmang, Thomas
A1  - Zimmermann, Ulrike
A1  - Syka, Josef
A1  - Knipper, Marlies
T1  - BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury
JF  - Molecular Neurobiology
N2  - For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF \(^{Pax2}\) -KO) versus the auditory cortex and hippocampus (BDNF \(^{TrkC}\) -KO). We demonstrate that BDNF \(^{Pax2}\) -KO but not BDNF \(^{TrkC}\) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF \(^{Pax2}\) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF \(^{Pax2}\) -KO, but not of BDNF \(^{TrkC}\) -KO mice. Also, BDNF \(^{Pax2}\) -WT but not BDNF \(^{Pax2}\) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.
KW  - Inner hair cell
KW  - Neurotropathic Factor
KW  - Hearing-loss
KW  - Alzheimers-disease
KW  - low-threshold fibers
KW  - cochlear nucleus neurons
KW  - Frequency-response areas
KW  - Inferior colliculus
KW  - Environmental enrichment
KW  - Synaptic plasticity
KW  - Cortical plasticity
KW  - BDNF
KW  - Central hyperactivity
KW  - High-spontaneous rate
KW  - Homeostatic plasticity
KW  - Sound detection threshold
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187341
VL  - 53
IS  - 8
ER  -