Indiana University-Purdue University Indianapolis (IUPUI) / Voltage-‐gated sodium channels (VGSCs) are critical for the initiation and propagation of electrical signals in neurons; consequently they are significant regulators of neuronal excitability. They are exquisitely tuned and aberrations in their activity can lead to pathophysiological conditions. This dissertation highlights the roles of two prominent brain isoforms of VGSCs, Nav1.1 and Nav1.6. These isoforms have distinct localization in the brain. Specifically, Nav1.1 is predominantly expressed in the soma and proximal axon initial segment (AIS) of GABAergic neurons, while Nav1.6 is found at the distal AIS and nodes of Ranvier of both GABAergic and excitatory neurons. Several mutations have been identified in Nav1.1 and recently mutations in Nav1.6 have been discovered in patients with distinct epileptic phenotypes that respond poorly to current anti-epileptics. There is a need to better understand mechanistically how mutations in these channel isoforms lead to epilepsy in order to identify more efficacious treatment strategies. Therefore, the aims of this dissertation were to 1) examine the differential biophysical properties of Nav1.1 and Nav1.6, 2) determine the biophysical consequences of epilepsy-associated mutations in Nav1.1 and Nav1.6 and examine the effects of cannabinoids on wildtype and mutant channel activity and 3) test the effects of selective inhibition of Nav1.1 versus Nav1.6 on epileptiform activity. To address these aims, whole‐cell electrophysiology and mutlielectrode array recordings were used. The results demonstrate that 1) Nav1.1 and Nav1.6 have important differences in their biophysical properties that may be important in the fine‐tuning of neuronal excitability, 2) epilepsy-‐associated mutations in Nav1.1 and Nav1.6 alter several biophysical properties of the channels but have differential effects on resurgent current generation suggesting a divergence in the mechanism by which they induce epileptogenesis and cannabidiol can inhibit aberrant channel activity and reduce neuronal excitability and 3) pharmacological inhibition of Nav1.6, but not Nav1.1, abolishes epileptiform activity. Overall, this dissertation provides insight into the distinct contributions of Nav1.1 and Nav1.6 to physiological and pathophysiological firing activity and their ability to be targeted for therapeutic purposes. This knowledge is critical for understanding the potential role of VGSCs in epilepsy syndromes and identifying possible drug targets for more efficacious treatment strategies.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/10637 |
| Date | 25 May 2016 |
| Creators | Patel, Reesha Rajni |
| Contributors | Cummins, Theodore R., Hudmon, Andy, Vasko, Michael R., Sheets, Patrick L., Jin, Xiaoming |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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