Dysmyelination of auditory afferent axons increases the jitter of action potential timing during high-frequency firing - PubMed (original) (raw)

Dysmyelination of auditory afferent axons increases the jitter of action potential timing during high-frequency firing

Jun Hee Kim et al. J Neurosci. 2013.

Abstract

Auditory neuropathies are linked to loss of temporal acuity of sound-evoked signals, which may be related to myelin loss. However, it is not known how myelin loss affects the waveform and temporal precision of action potentials (APs) in auditory CNS nerve terminals. Here we investigated the excitability of the calyx of Held nerve terminal in dysmyelinated auditory brainstems using the Long-Evans Shaker (LES) rat, a spontaneous mutant where compact myelin wrapping does not occur due to a genetic deletion of myelin basic protein. We found at relatively mature postnatal ages (15-17 d after birth) LES rat calyces showed prolonged spike latencies, indicative of a threefold reduction in the AP propagation velocity. Furthermore, LES rat afferent fiber-evoked APs showed a pronounced loss of temporal precision, even at low stimulation frequencies (10 Hz). While normal calyces were able to fire APs without failures at impressive rates of up to 1 kHz, LES calyces were unable to do so. Direct recordings of the presynaptic calyx terminal AP waveform revealed that myelin loss does not affect the AP spike upstroke and downstroke kinetics, but dysmyelination reduces the after-depolarization and enhances the fast after-hyperpolarization peak following the AP spike in the LES rat. Together these findings show that proper myelination is essential not only for fast AP propagation, but also for precise presynaptic AP firing that minimizes both spike jitter and failures, two characteristics critically important for the accurate processing of sound signals in the auditory brainstem.

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Figures

Figure 1.

Figure 1.

Expression of MBP in the rodent auditory brainstem increases with age. Fixed slices of auditory brainstem containing the ventral stria and MNTB were stained for myelin (MBP; green) and for synaptic vesicles (VGluT1; red). A, In normal young rats (LE rat; P5), sparse myelin is present in axonal projections. B, Soon after the onset of hearing (P13), myelin is highly expressed in MNTB axons, and terminates close to the calyx of Held presynaptic terminal. The arrow indicates the midline, where the bipolar stimulus electrode was placed. The areas containing the MNTB are indicated by dotted lines. C, Enlarged image of B, showing staining of presynaptic glutamatergic terminals and myelinated axons in the MNTB. D, Enlarged image of C, showing staining of presynaptic calyx-like terminals (yellow arrowheads) and myelinated axons in the MNTB. The white arrow shows a single isolated myelinated axon. E, A P17 mutant LES rat completely lacks staining for MBP, but synaptic vesicle staining (VGluT1; red) in the MNTB appears to be normal.

Figure 2.

Figure 2.

LES rats show increased presynaptic spike latency and a lack of temporal precision during 10 Hz repetitive firing. A, Afferent fiber stimulation at 10 Hz (10 stimulus pulses) results in presynaptic extracellular spikes when recorded in the cell-attached mode at a P17 calyx terminal: normal LE (black trace) and the LES mutant rat (red trace). Note the large latency shift (and temporal jitter) in the LES rat spikes (the labels first, second, and last indicate the order of responses to 10 Hz afferent fiber stimulation). One subthreshold trace is shown. B, Presynaptic action potentials from the same calyx recordings as shown in A in whole-cell current-clamp mode. Note the lack of precision (or jitter) in the timing of the spikes for LES mutants. C, Summary of the spike delay and jitter in LE and LES rats (**p < 0.001). S.A., stimulus artifact.

Figure 3.

Figure 3.

LES calyx terminals have a smaller ADP and an enhanced fAHP peak. Afferent fiber stimulation produced an action potential with an ADP in a P16 normal LE calyx recording (black; A) and an ADP with a reduced peak value in a calyx from the LES (right, red trace). Both calyces displayed an ADP (black arrowhead) and fAHP (red arrowhead). Inset, Same traces on an expanded voltage scale. B, Peak reversal voltage of fAHP was significantly larger in calyces from LES than LE, recorded from P15–P18 rats. C, Summary of the ADP amplitude, measured from resting potential to the peak of ADP in normal LE and mutant LES calyces in P15–P18 rats.

Figure 4.

Figure 4.

LES calyx terminals cannot follow APs at higher frequencies. AP trains were triggered at 100 Hz (A), 300 Hz (B), and 1 kHz (C) at room temperature (24°C, A and B) and at physiological temperature (PT; 37°C, C). The calyx of Held of both LE and LES rats can follow 100 Hz stimulation, but at higher stimulation frequencies (300 Hz and 1 kHz) presynaptic APs of the LES calyx terminals experience intermittent failures, whereas normal LE calyx terminals can routinely follow 300 Hz (at room temperature) and even 1 kHz at 37°C without AP failures. Recordings were from P16 LE and LES rats (black and red traces, respectively). The horizontal dashed line indicates the resting membrane potential of −80 mV. Arrowheads in B and blue arrows in C indicate AP failures. LES rats showed more AP failures and the timing of the APs showed more “jitter.”

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