Myelination in the auditory brainstem

The evolution of myelin was a major key event in vertebrates which aimed to enhance conduction velocity of electrical impulses in axons. Distinct myelination patterns along axons can shape the speed and timing of action potentials. Exact arrival time of inputs at target neurons are crucial for proper neural circuit function. Two key determinants for tuning conduction velocity of myelinated axons are the length of individual myelin sheaths together with the axon diameter. However, it remains unanswered who determines specific myelination patterns along axons – the oligodendrocyte or the axon? And further, when and how do structural parameters of myelinated axons develop in neural circuits in general, in terms of their functionally relevant myelination patterns, axonal morphology and nodes of Ranvier? A system with highest temporal demands is the mammalian sound localization system. Globular bushy cell (GBC) axons involved in circuits processing sound location information are some of the fastest and most precise conducting axons in the mammalian central nervous system. In the Mongolian gerbil (Meriones unguiculatus) GBCs that are tuned to low sound frequencies transmit sound signals to the binaural comparator neurons in the medial superior olive (MSO) where the arrival time of sound at the two ears (interaural time differences; ITDs) is computed. These differences can be as low as only a few microseconds and thus, computation of ITDs relies on explicitly fast and highly precise axons. To cope with the need for exact input timing, low-frequency GBC axons exhibit specific structural adaptations to adjust conduction velocity. Their exceptional thick axons combined with comparably short internodes result in unusual low ratios of internode length to axon diameter (L/d ratios) which in turn increase the conduction velocity along their axons. To gain insight into when and how the specific myelin sheath lengths, axon diameter and thus L/d ratios are established, we characterized the developmental time course of these structural parameters at timepoints before and after the onset of hearing. Our findings show the internode length is set prior to a significant axon diameter increase. While the internode length is established already two days before hearing onset, which is at P12, the axon diameter only increases five days after hearing onset, and thereby decreasing its L/d ratio. This strongly suggests that, at least in GBCs, the axon itself is the key determinant in ensuring that the required conduction velocity is met by adjusting its diameter retrospectively. Together with the length of myelin sheaths and the axon diameter, nodes of Ranvier are critical determinants of action potential speed and timing of and therefore the development of all these structures must be tightly regulated. By assessing the development of nodes of Ranvier we found that axon and node morphology by and large mature synchronously. Early nodal clusters appear already when myelination of GBC axons is initiated at P6/P7 and these premature clusters subsequently progress until reaching maturity during the 4th postnatal week. Interestingly, we were able to show that node maturation depends on the location along the axon with nodes closer to the cell body develop earlier compared to nodes close to the synaptic terminal

Distinct Distribution Patterns of Potassium Channel Sub-Units in Somato-Dendritic Compartments of Neurons of the Medial Superior Olive

Coincidence detector neurons of the medial superior olive (MSO) are sensitive to interaural time differences in the range of a few tens of microseconds. The biophysical basis for this remarkable acuity is a short integration time constant of the membrane, which is achieved by large low voltage-activated potassium and hyperpolarization-activated inward cation conductances. Additional temporal precision is thought to be achieved through a sub-cellular distribution of low voltage-activated potassium channel expression biased to the soma. To evaluate the contribution of potassium channels, we investigated the presence and sub-cellular distribution profile of seven potassium channel sub-units in adult MSO neurons of gerbils. We find that low- and high voltage-activated potassium channels are present with distinct sub-cellular distributions. Overall, low voltage-activated potassium channels appear to be biased to the soma while high voltage-activated potassium channels are more evenly distributed and show a clear expression at distal dendrites. Additionally, low voltage-activated potassium channel sub-units co-localize with glycinergic inputs while HCN1 channels co-localize more with high voltage-activated potassium channels. Functionally, high voltage-activated potassium currents are already active at low voltages near the resting potential. We describe a possible role of high voltage-activated potassium channels in modulating EPSPs in a computational model and contributing to setting the integration time window of coincidental inputs. Our data shows that MSO neurons express a large set of different potassium channels with distinct functional relevance

Distinct Distribution Patterns of Potassium Channel Sub-Units in Somato-Dendritic Compartments of Neurons of the Medial Superior Olive

Coincidence detector neurons of the medial superior olive (MSO) are sensitive to interaural time differences in the range of a few tens of microseconds. The biophysical basis for this remarkable acuity is a short integration time constant of the membrane, which is achieved by large low voltage-activated potassium and hyperpolarization-activated inward cation conductances. Additional temporal precision is thought to be achieved through a sub-cellular distribution of low voltage-activated potassium channel expression biased to the soma. To evaluate the contribution of potassium channels, we investigated the presence and sub-cellular distribution profile of seven potassium channel sub-units in adult MSO neurons of gerbils. We find that low- and high voltage-activated potassium channels are present with distinct sub-cellular distributions. Overall, low voltage-activated potassium channels appear to be biased to the soma while high voltage-activated potassium channels are more evenly distributed and show a clear expression at distal dendrites. Additionally, low voltage-activated potassium channel sub-units co-localize with glycinergic inputs while HCN1 channels co-localize more with high voltage-activated potassium channels. Functionally, high voltage-activated potassium currents are already active at low voltages near the resting potential. We describe a possible role of high voltage-activated potassium channels in modulating EPSPs in a computational model and contributing to setting the integration time window of coincidental inputs. Our data shows that MSO neurons express a large set of different potassium channels with distinct functional relevance

Development of myelination and axon diameter for fast and precise action potential conductance

Axons of globular bushy cells in the cochlear nucleus convey hyper-accurate signals to the superior olivary complex, the initial site of binaural processing via comparably thick axons and the calyx of the Held synapse. Bushy cell fibers involved in hyper-accurate binaural processing of low-frequency sounds are known to have an unusual internode length-to-axon caliber ratio (L/d) correlating with higher conduction velocity and superior temporal precision of action potentials. How the L/d-ratio develops and what determines this unusual myelination pattern is unclear. Here we describe a gradual developmental transition from very simple to complex, mature nodes of Ranvier on globular bushy cell axons during a 2-week period starting at postnatal day P6/7. The molecular composition of nodes matured successively along the axons from somata to synaptic terminals with morphologically and molecularly mature nodes appearing almost exclusively after hearing onset. Internodal distances are initially coherent with the canonical L/d-ratio of ~100. Several days after hearing onset, however, an over-proportional increase in axon caliber occurs in cells signaling low-frequency sounds which alters their L/d ratio to ~60. Hence, oligodendrocytes initially myelinating axons according to their transient axon caliber but a subsequent differential axon thickening after hearing onset results in the unusual myelination pattern