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Haßfurth, Benjamin (2010): ACTIVITY-DEPENDENT CHANGES IN A NEURONAL CIRCUIT IMPORTANT FOR SOUND LOCALIZATION. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)



Aside from recognizing and distinguishing sound patterns, the ability to localize sounds in the horizontal plane is an essential component of the mammalian auditory system. It facilitates approaching potential mating partners and allows avoiding predators. The superior olivary complex (SOC) within the auditory brainstem is the first site of binaural interaction and its major projections and inputs are well investigated. The adult input pattern, however, is not set from the beginning but changes over the period of development. Mammals including humans experience different stages and conditions of hearing during auditory development. The human brain for instance has to perform a transition after birth from the perception of sound waves transmitted in amniotic fluid to the perception of airborne sounds. Furthermore, small mammals like rodents, which are common model organisms for auditory research, perceive airborne sounds for the first time some days after birth, when their ear canals open. The basic neuronal projections and the intrinsic properties of neurons, such as the expression of specific ion channels, are already established and adjusted in the SOC during the perinatal period of partial deafness. An additional refinement of inputs and further adaptations of intrinsic characteristics occur with the onset of hearing in response to the new acoustic environment. It is likely that with ongoing maturation well-established inputs within the sound localization network need these adaptations to balance anatomical changes such as an increasing head size. In addition, short-term adjustments of synaptic inputs in the adult auditory system are equally necessary for a faithful representation of auditory space. A recent study suggests that these short-term adaptations are partially represented at the auditory brainstem level. The question of how intrinsic properties change during auditory development, to what extent auditory experience is involved in these changes and the functional implications of these changes on the sound localization circuitry is only partially answered. I used the hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN channels), which are a key determinant of the intrinsic properties of auditory brainstem neurons, as a target to study the influence of auditory experience on the intrinsic properties of neurons in the auditory brainstem. Another important question still under discussion is how neurons in the auditory brainstem might fine-tune their firing behavior to cope optimally with an altered acoustic environment. Recent data suggest that auditory processing is also affected by modulatory mechanisms at the brainstem level, which for instance change the input strength and thus alter the spike output of these neurons. One possible candidate is the metabotropic GABAB receptor (GABABR) which has been shown to be abundant in the adult auditory brainstem, although GABAergic projections are scarce in the mature auditory brainstem. These questions were investigated by performing whole-cell patch-clamp recordings of SOC neurons from Mongolian gerbils at different developmental stages in the acute brain slice preparation. Specific currents and receptors were isolated using pharmacological means. Immmunohistochemical results additionally supported physiological findings. In the first study, I investigated the developmental regulation of HCN channels in the SOC and their underlying depolarizing current Ih, which has been shown to regulate the excitability of neurons and to enhance the temporally precise analysis of binaural acoustic cues. I characterized the developmental changes of Ih in neurons of the lateral superior olive (LSO) and the medial nucleus of the trapezoid body (MNTB), which in the adult animals show different HCN subunit composition. I showed that right after hearing onset there was a strong increase of Ih in the LSO and just a minor increase in the MNTB. In addition, the open probability of HCN channels was shifted towards more positive voltages in both nuclei and the activation time constants accelerated during the first days of auditory experience. These results implicate that Ih is actively regulated by sensory input activity. I tested this hypothesis by inducing auditory deprivation which was achieved by surgically removing the cochlea in gerbils before hearing onset. The effect was opposite in neurons of the MNTB and the LSO. Whereas in LSO neurons auditory deprivation resulted in increased Ih amplitude, MNTB neurons displayed a moderate decrease in Ih. These results suggest that auditory experience differentially changes the amount of HCN channels dependent on the subunit composition or possibly alters intracellular cAMP levels, thereby shifting the voltage dependence of Ih. This regulatory mechanism might thus maintain adequate excitability levels within the SOC. A second study was carried out to investigate the role of GABABRs in the medial superior olive (MSO). Upon activation, these metabotropic receptors are known to decrease the release probability of neurotransmitters at the presynapse thereby altering excitatory and inhibitory currents at the postsynaptic site. Neurons in the MSO analyze interaural time differences (ITDs) by comparing the relative timing of the excitatory inputs from the two ears using a coincidence mechanism. In addition, these neurons receive a precisely timed inhibitory input from each ear which shifts ITDs in the physiological relevant range. Since the major inhibitory input changes its transmitter type from mixed GABA/glycinergic to only glycinergic after hearing onset it was now interesting to examine the mediated effects of GABABRs, which have been shown to be abundant in the prehearing and adult MSO of gerbils. Furthermore, revealing the precise expression pattern of GABABRs and their influence on excitatory and inhibitory currents in the MSO during auditory development should provide further evidence of their functional relevance. Performing pharmacological experiments I could now demonstrate that the activation of GABABRs before hearing onset decreases the current of excitatory inputs stronger than that of inhibitory inputs whereas a switch is performed after hearing onset and inhibitory currents are stronger decreasedcompared to excitatory currents. In a similar way, also the expression pattern of GABABRs changes before and after hearing onset as revealed by immunohistochemistry. Since the main inhibitory inputs to the adult MSO are purely glycinergic, it was commonly assumed that GABABRs occupy only a minor role in the mature auditory brainstem. Contradictory to this, it was possible to activate presynaptic GABABRs by synaptic stimulation even in adult animals and to observe a profound decrease of inhibitory current in MSO neurons. These results suggest GABAergic projections of yet unknown origin targeting the MSO. It is therefore quite likely that GABABRs modulate and possibly improve the localization of low frequency sounds even in adult mammals. Summarized, the outcome of this thesis contributes to a better understanding of the developmental adaptation in the auditory system and demonstrates that the orderly specification of intrinsic properties within the SOC is dependent on auditory experience. Moreover, I show that even in mature animals the synaptic strength of MSO inputs can be modulated by synaptic GABA release. This should emphasize the importance of modulatory mechanisms and could be the basis for future studies concerning the field of sound localization.