Tonotopic action potential tuning of maturing auditory neurons through endogenous ATP

Abstract

Synaptic refinement and strengthening are activity dependent processes that establish orderly arranged cochleotopic maps throughout the central auditory system. The maturation of auditory brainstem circuits is guided by action potentials (APs) arising from the inner hair cells in the developing cochlea. The AP firing of developing central auditory neurons can be modulated by paracrine ATP signaling, as shown for the cochlear nucleus bushy cells and principal neurons in the medial nucleus of the trapezoid body. However, it is not clear whether neuronal activity may be specifically regulated with respect to the nuclear tonotopic position, i.e. sound frequency selectivity. Using slice recordings before hearing onset and in vivo recordings with iontophoretic drug applications after hearing onset we show that cell-specific purinergic modulation follows a precise tonotopic pattern in the ventral cochlear nucleus of developing gerbils. In high-frequency regions, ATP responsiveness diminished before hearing onset. In low-to-mid frequency regions, ATP modulation persisted after hearing onset in a subset of low-frequency bushy cells (CF<10 kHz). Down-regulation of P2×2/3R currents along the tonotopic axis occurs simultaneously with an increase in AMPAR currents, thus suggesting a high-to-low frequency maturation pattern. Facilitated AP generation, measured as higher firing frequency, shorter EPSP-AP delay in vivo, and shorter AP latency in slice experiments, is consistent with increased synaptic efficacy caused by ATP. Finally, by combining recordings and pharmacology in vivo, in slices, and in HEK cells it was shown that the long lasting change in intrinsic neuronal excitability is mediated by the P2×2/3R.

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