Abstract
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 (BDNFPax2-KO) versus the auditory cortex and hippocampus (BDNFTrkC-KO). We demonstrate that BDNFPax2-KO but not BDNFTrkC-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 BDNFPax2 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 BDNFPax2-KO, but not of BDNFTrkC-KO mice. Also, BDNFPax2-WT but not BDNFPax2-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.
Highlights
Brain-derived neurotrophic factor (BDNF) was initially identified as a survival factor for peripheral neurons
To define the source of BDNF that is responsible for the absence of normal hearing thresholds of BDNFPax2-KO animals [25], we compared the auditory phenotype of BDNF-Pax2Cre transgenic mice with that of BDNF-TrkC-Cre mice, in which the Cre gene is controlled by the TrkC promoter [26]
We show here that BDNF present in the lower parts of the auditory CNS or the peripheral end organ improves the threshold for sound and the dynamic range of sound responses
Summary
Brain-derived neurotrophic factor (BDNF) was initially identified as a survival factor for peripheral neurons (reviewed in [1, 2]). As constitutive BDNF knockout (KO) mice [18, 19] die too prematurely to assess the role of BDNF in the mature sensory organs, the role of peripheral versus central BDNF for sensory resolution and acuity is still obscure Until now, it remains unclear if and how these crucial effects of BDNF during the development of normal sensory function are linked to the complex changes of BDNF activity in mature systems, which have been described as either adaptive responses to injury [20] or nonadaptive responses in various brain disorders [21]
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