Browsing by Author "Frazee, Ashley"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Differential Regulation of Nav1.1 and SCN1A Disease Mutant Sodium Current Properties by Fibroblast Growth Factor Homologous Factors
    (MDPI, 2025-02-15) Frazee, Ashley; Zybura, Agnes; Cummins, Theodore R.; Biology, School of Science
    Fibroblast growth factor homologous factors (FHFs) regulate the activity of several different voltage-gated sodium channels (Navs). However, more work is needed to determine how specific FHF isoforms and variants affect the properties of different Nav isoforms. In addition, it is not known if FHFs can differentially modulate the properties of Nav variants associated with disease. Here, we investigated the effects of FHF2A and FHF2B on Nav1.1 properties as well as on a familial hemiplegic migraine 3 (FHM3) causing mutation in this channel, F1774S. We found that FHF2A, but not 2B, induced prominent long-term inactivation (LTI) in the wild-type (WT) Nav1.1. Interestingly, FHF2A induced LTI in the F1774S FHM3 mutant channel to a greater extent than in the WT. Furthermore, persistent currents caused by the F1774S mutation were attenuated by the co-expression of FHF2A, leading to a possible rescue of the mutant channel phenotype. By contrast, the P1894L mutation, which is associated with epilepsy and mild intellectual disability, greatly attenuated the LTI induced by FHF2A. Overall, our data show for the first time that FHF2A might be a significant modulator of Nav1.1 that can differentially modulate the impact of Nav1.1 disease-associated mutations.
  • Thumbnail Image
    Item
    Investigating the Modulation of Voltage-Gated Sodium Channel Nav1.1 Neuronal Excitability by Fibroblast Growth Factor Homologous Factor 2 and Il-6
    (2023-12) Frazee, Ashley; Cummins, Theodore; Berbari, Nicolas; Baucum, A.J.; Boehm, Stephen
    Migraine is a condition that has affected many for generations and yet remains poorly understood. Mutations to the Nav1.1 voltage gated sodium channels have been implicated in various diseases such as Familial Hemiplegic Migraine 3 (FHM3), epilepsy, and autism spectrum disorder (ASD). Various proteins have been found to modify the function of these channels. Fibroblast growth factor homologous factors (FHFs) have been found to regulate the activity of some voltage-gated sodium channels (Navs). More work is needed to determine which FHFs affect which Navs. Here I looked at FHF2A and FHF2B in Nav1.1 as well as an FHM3-causing mutation to this channel, F1774S. I found that FHF2A, but not 2B, induced long-term inactivation (LTI) in the wild-type (WT) Nav1.1 and that FHF2A induced LTI in the F1774S mutant channel to a greater extent. Several changes in channel function caused by the mutation were attenuated with the addition of FHF2A, including persistent currents, leading to a possible rescue in the mutant phenotype. By contrast, the P1894L mutation, which has been found to cause ASD, greatly attenuated LTI and other impacts of FHF2A on Nav1.1. The inflammatory cytokine IL-6 was also investigated as a possible modulator of the Nav1.1 channel. There does not appear to be any direct interaction between this cytokine and the channel. Overall, my data shows for the first time that FHF2A, but FHF2B or IL-6, might be a significant modulator of Nav1.1 and can differentially modulate disease mutations.
  • Thumbnail Image
    Item
    Modelling Nicotine Self-Administration Using Drinking-in-the-Dark
    (Office of the Vice Chancellor for Research, 2015-04-17) Frazee, Ashley; Kasten, Chelsea; Boehm, Stephen
    Although cigarette smoking is a widely recognized problem in the United States, few animal models of nicotine self-administration exist. One aim of this study was to develop a new model of nicotine selfadministration in animals. The Drinking in Dark (DID) model, in which ethanol access is given for two hours, three hours into the dark cycle, can be easily altered to investigate nicotine intake and withdrawal. We found that animals will readily consume around 6 mg/kg of nicotine per day, which is equivalent to smoking approximately 3-4 cigarettes. A second aim of the study was to test pharmacological manipulations in the model. Two areas of focus for pharmaceutical manipulations involve GABA and acetylcholine. On the fifth day of nicotine DID we administered baclofen, a GABAB receptor agonist, or mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, immediately prior to nicotine consumption. We found that baclofen, but not mecamylamine, reduced nicotine intake (p < .05). The final aim of the study will be to test for face validity of the model. A separate group of mice will be given access to nicotine or saccharin for 5 or 10 days using DID procedures. Face validity of the model will be tested using the elevated plus maze and by observing locomotor activity during spontaneous withdrawal, approximately 55 hours following the last DID presentation. Taken together, these studies suggest that nicotine DID is a valid model of voluntary nicotine intake that can be tested for smoking treatments, as well as the neurobiological underpinnings of repeated nicotine use.