Thompson, Roger J.Tucker, Catharine M.2021-01-252021-01-252021-01-13Tucker, C. M. (2021). Pannexin-1 suppresses network excitability in a TRPV1-dependent manner (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.http://hdl.handle.net/1880/113003Epilepsy is characterized by recurrent seizures, which disrupt brain function. Deviations in neuronal excitability and imbalances in excitation and inhibition have been shown to promote seizure generation. However, the molecular determinants of these alterations remain elusive. Pannexin-1 (Panx1), the large pore ion/metabolite channel, has been recognized as a molecular hub in epileptogenesis. However, the mechanisms by which Panx1 affects excitation and/or inhibition are not clearly understood. Previous findings from our lab suggest that blocking Panx1 enhances the excitatory tone in CA1 pyramidal neurons following afferent stimulation. We also found that Panx1 ablation exacerbates epileptogenesis in an electrical kindling model of seizures. Here, I propose to determine how blocking Panx1 alters neuronal excitability and whether it plays a role in epileptiform activity. This thesis will explore if inhibiting functional Panx1 pushes neuronal excitability towards a more easily excitable seizure-prone state. The overall hypothesis is that blocking Panx1 promotes epileptiform activity by enhancing neuronal network excitability. Here, we report that Panx1 inhibition promotes burst firing in the hippocampus following afferent stimulation. This bursting effect was found to operate in a transient receptor potential vanilloid-1 (TRPV1)-dependent manner. Pharmacological block and genetic ablation of TRPV1 was found to ameliorate this effect. We also report that removing Panx1 function has no significant effect on intrinsic neuronal excitability. Recognizing Panx1 channel involvement in balancing excitability in the brain may give rise to a new therapeutic target to reduce aberrant neuronal activity. As a third of epileptic patients experience pharmacoresistant epilepsy, understanding the mechanisms of synaptic communication that change a healthy brain into a seizure-prone brain can provide insight into novel targets for the prevention of neuronal hyperexcitability. Determining a full mechanism of synaptic modifications that leads to a hyperexcitable brain could be beneficial for drug development that can lead to better treatments and overall patient outcomes.  University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.ElectrophysiologyPannexin-1BiologyNeurosciencemaster thesis10.11575/PRISM/38571