Functional Analysis of The ATP-Release Channel Pannexin1 in Mouse and Zebrafish Models: Implications for Health and Disease

Pannexin1 (Panx1) is a large membrane channel protein with complex gating mechanisms permeable to ions, glutamate, and ATP. Panx1 is ubiquitously expressed throughout the central nervous system, exposing the channel to dynamic molecular, structural, ionic, and electrical changes in neurons or glial cells. The release of signaling molecules from Panx1 channels has been linked to synaptic plasticity, learning and memory, and sensory system function. Evidence also supports purinergic signaling via Panx1 in pathophysiological conditions like epilepsy, ischemia, inflammation, and pain. Here, conflicts in the literature regarding (patho)physiological roles of Panx1 using an interdisciplinary approach are addressed. The motivation for each step, moving from in vitro cell models with overexpression of Panx1 to networks or whole system levels in Panx1-/- mice and Panx1-/- zebrafish, is to prove how Panx1 and ATP mediated signaling affects olfaction, visual processing, and seizures. A key finding dismisses the role of mouse Panx1 in olfaction but leads to the identification of a compensatory mechanism. The global loss of Panx1 (Panx1-/-) in mice is compensated by the upregulation of Panx3. The roles of Panx1 in the processing of visual stimuli are investigated in the intact retinotectal pathway of the zebrafish. The loss of the zebrafish panx1 ohnologs, panx1a and panx1b, leads to distinct responses to light stimuli. The results suggest that each pannexin type contributes differently to primary vision, most likely based on the localization of the channels in the retinotectal network and differences in channel properties. Finally, the conflict in the literature about pro- and anti-convulsant properties of Panx1 is addressed in the zebrafish. Prior investigations demonstrated pro-convulsant roles of Panx1 in the mouse. The principal outcome of the study in the zebrafish model demonstrates that Panx1a channels have pro-convulsant properties in vivo that p2rx7 and ATP signaling mediate. However, Panx1b channels in the absence of Panx1a improves seizure outcomes. The discovery of dual roles of Panx1 channels in the zebrafish provides unique opportunities to study the molecular basis of seizures from genes to organisms and to use it as an anti-convulsant drug discovery model. In summary, the findings in this thesis are a multifaceted approach towards resolving neurobiological questions from the perspective of Panx1 in health and disease.