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Conspecific chemosensory communication controls a broad range of social and sexual behaviors. In most mammals, social chemosignals are predominantly detected by sensory neurons of a specialized olfactory subsystem, the vomeronasal organ (VNO). The behavioral relevance of social chemosignaling puts high demands on the accuracy and dynamic range of the underlying transduction mechanisms. However, the physiological concepts implemented to ensure faithful transmission of social information remain widely unknown. The overall goal of my thesis was to uncover molecular and physiological concepts underlying pheromone signaling in the mouse VNO. To address these issues, I focused on three specific projects addressing vomeronasal plasticity (a), adaptation (b), and peripheral activity correlated to olfactory learning (c). My first goal was to investigate whether vomeronasal sensory neurons (VSNs) control their input-output relationships by activity-regulated expression of specific ion channels (homeostatic plasticity). Here, I report the activity-dependent expression of an ether-à-gogo related gene (ERG) ion channel in basal vomeronasal sensory neurons (VSNs) of mice. Patch-clamp recordings from basal VSNs in acute VNO slices showed that ERG-mediated currents are activated during action potential (AP) discharge. Pharmacological block or deprivation-dependent down-regulation of ERG channels strongly diminished tonic firing in response to depolarizing current injections. Thus, these data indicate an important role of ERG channels in extending the dynamic response range of basal VSNs, revealing a previously unknown form of intrinsic plasticity in the VNO. In olfactory sensory neurons, as well as in most other sensory systems, the entire (chemo)transduction process adapts in response to saturating and/or prolonged stimulation, thus, adjusting the neuronal sensitivity range. Previous studies, however, claimed that VSNs represent an exception to that ‘rule’, i.e. they fail to adapt. Therefore, my second goal was to investigate a potential feedback modulation in VSN signaling. Here, I report that VSN responses undergo effective sensory adaptation that requires the influx of Ca2+ and is mediated by calmodulin (CaM). Removal of the Ca2+-CaM feedback eliminated pheromone adaptation. These data reveal a previously unrecognized feedback mechanism that is essential for adjusting the sensitivity of pheromone detection in the VNO. Pheromonal exposure can induce robust single-trial memory mediated by the vomeronasal system. Therefore, my third goal was to investigate this phenomenon on the level of AP firing and cytosolic Ca2+ signals. Here, I observed unusual temporal response features in VSNs. Electrophysiological recordings revealed persistent AP discharge after brief exposure to pheromonal cues in a subset of VSNs. A similar pattern was detected in imaging experiments that revealed long-lasting Ca2+-oscillations. This temporal response phenomenon could also be induced indirectly by Ca2+-store depletion. Pharmacological experiments revealed a role of voltage-gated L-type Ca2+-channels. Although, the mechanisms of sustained activity in VSNs have to be investigated in detail in future experiments, these data indicate an important role of persistent and regenerative VSN output patterns for olfactory memory. Together, the data presented in this thesis reveal a fundamental function of activity-dependent gene expression (homeostatic plasticity), Ca2+-CaM-dependent response adaptation, and sustained activity patterns in VSNs. Therefore, gain control and fine-tuning of input-output relationships in VSNs may have a crucial impact on social behavior in mice. |
