Abstract
Principal neurons of the lateral superior olive (LSO) compute the interaural intensity differences necessary for localizing high-frequency sounds. To perform this computation, the LSO requires precisely tuned, converging excitatory and inhibitory inputs that are driven by the two ears and that are matched for stimulus frequency. In rodents, the inhibitory inputs, which arise from the medial nucleus of the trapezoid body (MNTB), undergo extensive functional refinement during the first postnatal week. Similar functional refinement of the ascending excitatory pathway, which arises in the anteroventral cochlear nucleus (AVCN), has been assumed but has not been well studied. Using whole-cell voltage clamp in acute brainstem slices of neonatal rats, we examined developmental changes in input strength and pre- and post-synaptic properties of the VCN-LSO pathway. A key question was whether functional refinement in one of the two major input pathways might precede and then guide refinement in the opposite pathway. We find that elimination and strengthening of VCN inputs to the LSO occurs over a similar period to that seen for the ascending inhibitory (MNTB-LSO) pathway. During this period, the fractional contribution provided by NMDA receptors (NMDARs) declines while the contribution from AMPA receptors (AMPARs) increases. In the NMDAR-mediated response, GluN2B-containing NMDARs predominate in the first postnatal week and decline sharply thereafter. Finally, the progressive decrease in paired-pulse depression between birth and hearing onset allows these synapses to follow progressively higher frequencies. Our data are consistent with a model in which the excitatory and inhibitory projections to LSO are functionally refined in parallel during the first postnatal week, and they further suggest that GluN2B-containing NMDARs may mediate early refinement in the VCN-LSO pathway.
Highlights
The superior olivary complex in the auditory brainstem includes the key nuclei responsible for azimuthal sound localization
The excitatory, glutamatergic projection arises in the ipsilateral anteroventral cochlear nucleus (AVCN) [4,5], whereas the inhibitory, glycinergic projection arises in the ipsilateral medial nucleus of the trapezoid body (MNTB), a sign-inverting nucleus driven by the contralateral VCN [6,7,8,9]
In P11-12 neurons, ifenprodil had almost no effect on either peak current amplitude or charge transfer (% reduction of current amplitude in ifenprodil: P1-2, 61.466.6%, n = 5; postnatal day 3 (P3)-4, 59.464.4%, n = 8; P5-6, 54.364.3%, n = 6; P7-8, 41.768.2%, n = 6; P9-10, 17.863.8%, n = 6; P11-12, 6.462.2%, n = 5; % reduction of charge transfer in ifenprodil: P1-2, 59.267.6%; P3-4, 59.064.7%; P5-6, 55.064.3%; P7-8, 41.866.5%; P9-10, 18.864.9%; P11-12, 24.664.6%). These findings indicate that maturation of synaptic currents in the VCN-lateral superior olive (LSO) pathway is due not solely to an increase in the ratio of AMPA receptors (AMPARs) to NMDA receptors (NMDARs), and to a subunit switch in the NMDARs at the end of the first postnatal week
Summary
The superior olivary complex in the auditory brainstem includes the key nuclei responsible for azimuthal sound localization. A question of fundamental importance is how these primary inputs of opposing sign are coordinately refined during development to provide the finescale tuning necessary for computing interaural level differences in the adult LSO (for reviews, see [10,11]). Axons of both excitatory and inhibitory projections can be detected in the LSO shortly before birth in the rat [12]. It has often been assumed that during this same period the ipsilateral VCN inputs to the LSO undergo developmental refinement, much less is known about how the VCN-LSO pathway normally develops
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