John A Wemmie
University Of Iowa
Project start date: 2009-04-16
Project end date: 2014-02-28
Sponsored Links Excellgen http://Excellgen.com
MODELING CO2-EVOKED FEAR IN MICE: ROLE OF ACID-SENSING ION CHANNELS
John A Wemmie, Assistant Professor
University Of Iowa, Iowa City, Ia 52242
Grant 5R01MH085724-02 from National Institute Of Mental Health
Abstract: Anxiety disorders are the most common form of psychiatric illness and exact a huge toll on America´s health. Current treatments are often inadequate suggesting more effective, more specific therapies are needed. Clinical studies have firmly established that CO2 inhalation triggers anxiety and panic attacks, and that patients with anxiety disorders are hyper-responsive to CO2. These findings suggest that a better understanding of the molecular mechanisms underlying CO2 sensitivity could lead to novel insight into the causes of anxiety disorders and possibly lead to better treatments. Because CO2 sensitivity has been explored primarily in clinical studies, which are restricted in their ability to identify molecular mechanisms, there is a significant need for animal models to probe the mechanisms underlying CO2 sensitivity. In this proposal we address this need for animal models of CO2-evoked fear, by modeling CO2 behavioral and physiological responses in mice. We investigate the hypothesis that CO2 inhalation lowers brain pH, which activates pH-sensitive receptors in the fear circuit, which in turn increase the behavioral and physiological manifestations of fear, anxiety, and panic. This project may be critical for helping to explain the long recognized, but poorly understood clinical phenomenon of CO2 sensitivity. In addition, these studies are likely to have broader implications. Our preliminary data suggest that CO2 activates novel signaling pathways underlying anxiety disorders, and that these pathways might be therapeutically targeted to prevent anxiety disorders and reduce their symptoms. Although it is well established that carbon dioxide (CO2) inhalation triggers anxiety and panic in anxiety disorder patients, the underlying mechanisms are not known. This proposal models CO2- evoked anxiety and panic in mice and suggests that understanding CO2-sensitivity has broad implications, including novel molecular pathways underlying anxiety disorders and new treatment targets
Keywords: No Project Terms available
Relevance: . Although it is well established that carbon dioxide (CO2) inhalation triggers anxiety and panic in anxiety disorder patients, the underlying mechanisms are not known. This proposal models CO2- evoked anxiety and panic in mice and suggests that understanding CO2-sensitivity has broad implications, including novel molecular pathways underlying anxiety disorders and new treatment targets
Project start date: 2009-04-16
Project end date: 2014-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-07-070
5R01MH085724-02 (2010): $372449
Grants awarded to John A Wemmie
INHIBITION OF SEIZURES AND NEURON EXCITABILITY BY ACID-SENSING ION CHANNELS
John A Wemmie, Assistant Professor
University Of Iowa, Iowa City, Ia 52242
Grant 5R21NS058309-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Seizure disorders cause significant morbidity and mortality, and many cases are refractory to current medical management. Thus, improved treatments are needed. Therapeutic advances might be developed from a better understanding of the antiepileptic mechanisms of brain acidosis. It has long been known that low pH effectively inhibits seizures and reduces neuron excitability, but the molecular mechanisms underlying these effects are poorly understood. The recent identification of proton receptors in the brain may provide a molecular link between brain pH and seizures. It was recently found that one of these receptors, the acid sensing ion channel ASIC1a is required for acid-evoked currents in central neurons. And consistent with an inhibitory effect on seizures, preliminary data indicate overexpressing ASIC1a in mice attenuates seizures. In contrast, disrupting ASIC1a makes seizures worse. Together, these observations suggest the hypothesis that ASIC1a mediates the antiepileptic effects of central acidosis and reduces neuron excitability. To test this hypothesis three aims are planned. The first aim will test whether ASIC1a mediates antiepileptic effects of CO2, which rapidly crosses the blood-brain barrier and lowers central pH. Wild-type mice, ASIC1a null mice, and ASIC1a overexpressing transgenic mice will be injected with a chemoconvulsant and the anti-epileptic effects of CO2 relative to air will be compared between genotypes. The results will provide an indication of whether the anti-epileptic properties of ASIC1a and CO2 are related. The second aim will test whether ASIC1a mediates the antiepileptic effects of acid in brain slices where pH can be better controlled. The third aim will test the effects of ASIC1a on acid inhibition of action potentials in cultured hippocampal neurons. Preliminary data suggest ASIC1a may inhibit action potentials, which may help explain how ASIC1a inhibits seizures in vivo. Together these experiments will provide important insight into the historically well established but poorly understood antiepileptic effects of acid. They will also lead to additional mechanistic studies to clarify in more depth how ASIC1a exerts its antiepileptic effects. Importantly, these studies may also suggest ASIC1a as a novel therapeutic target for inhibiting seizures in patients. Identifying novel and broad antiepileptic mechanisms may be especially beneficial to patients with refractory disease. Seizures disorders cause significant morbidity and mortality and are often refractory to medical management. Studying novel features of seizure inhibition may lead to treatments with alternative mechanisms of action. In this application we explore the seizure inhibiting effects of a poorly understood gene, acid-sensing ion channel 1a, and we test whether ASIC1a contributes to the well-established but poorly understood antiepileptic effects of brain acidosis. These studies have the potential to foster the development of Asic1a antagonists as a novel therapeutic approach to seizures
Keywords: ASIC channel; Acidosis; Acids; Action Potentials; Affect; Air; Ammon Horn; Anti-epileptic; Antiepileptic Agents; Antiepileptic Drugs; Antiepileptics; Aspiration, Respiratory; Attenuated; Biological Models; Blood - brain barrier anatomy; Blood-Brain Barrier; Brain; Breathing; CO2; Carbon Dioxide; Carbonate Dehydratase Inhibitors; Carbonic Anhydrase Inhibitors; Carbonic Anhydride; Carboxyanhydrase Inhibitors; Cells; Cornu Ammonis; DNA Alteration; DNA mutation; Data; Deep; Depth; Development; Disease; Disorder; EEG; Electroencephalography; Encephalon; Encephalons; Epilepsy; Epileptic Seizures; Epileptics; Fostering; Gene Alteration; Gene Mutation; Generations; Genes; Genetic mutation; Genotype; Goals; H+ element; Hemato-Encephalic Barrier; Hippocampus; Hippocampus (Brain); Human; Human, General; Hydrogen Ions; Inhalation; Inhaling; Inspiration, Respiratory; Investigators; Ion Channel; Ion Channels, Potassium; Ionic Channels; K channel; Kinetic; Kinetics; Knock-out; Knockout; Knockout Mice; Knowledge; Laboratories; Lead; Link; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Mediating; Medical; Membrane Channels; Membrane Potentials; Mice; Mice, Knock-out; Mice, Knockout; Mice, Transgenic; Model System; Models, Biologic; Molecular; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Murine; Mus; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neurons; Null Mouse; Numbers; Overexpression; Patients; Pb element; Play; Position; Positioning Attribute; Potassium Channel; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Protein Overexpression; Protons; Range; Receptor Protein; Refractory; Refractory Disease; Relative; Relative (related person); Research; Research Personnel; Researchers; Resting Potentials; Role; Seizure Disorder; Seizures; Sequence Alteration; Severities; Slice; Source; Testing; Therapeutic; Transgenic Mice; Transmembrane Potentials; Wild Type Mouse; Work; acid-sensing ion channels; disease/disorder; epilepsia; epileptiform; epileptogenic; experiment; experimental research; experimental study; extracellular; heavy metal Pb; heavy metal lead; hippocampal; improved; in vivo; insight; inspiration; interest; neuronal; new therapeutics; next generation therapeutics; novel; novel therapeutics; overexpress; prevent; preventing; programs; receptor; research study; response; social role; therapeutic target
Project start date: 2007-09-14
Project end date: 2010-06-30
Budget start date: 1-JUL-2008
Budget end date: 30-JUN-2010
PFA/PA: PA-06-190
5R21NS058309-02 (2008): $0
1R21NS058309-01A1 (2007): $193594
Modeling CO2-evoked Fear In Mice: Role Of Acid-sensing Ion Channels
John A Wemmie
Psychiatryuniversity Of Iowa
Grant 1R01MH085724-01 from National Institute Of Mental Health IRG: ZRG1
Abstract: Anxiety disorders are the most common form of psychiatric illness and exact a huge toll on America´s health. Current treatments are often inadequate suggesting more effective, more specific therapies are needed. Clinical studies have firmly established that CO2 inhalation triggers anxiety and panic attacks, and that patients with anxiety disorders are hyper-responsive to CO2. These findings suggest that a better understanding of the molecular mechanisms underlying CO2 sensitivity could lead to novel insight into the causes of anxiety disorders and possibly lead to better treatments. Because CO2 sensitivity has been explored primarily in clinical studies, which are restricted in their ability to identify molecular mechanisms, there is a significant need for animal models to probe the mechanisms underlying CO2 sensitivity. In this proposal we address this need for animal models of CO2-evoked fear, by modeling CO2 behavioral and physiological responses in mice. We investigate the hypothesis that CO2 inhalation lowers brain pH, which activates pH-sensitive receptors in the fear circuit, which in turn increase the behavioral and physiological manifestations of fear, anxiety, and panic. This project may be critical for helping to explain the long recognized, but poorly understood clinical phenomenon of CO2 sensitivity. In addition, these studies are likely to have broader implications. Our preliminary data suggest that CO2 activates novel signaling pathways underlying anxiety disorders, and that these pathways might be therapeutically targeted to prevent anxiety disorders and reduce their symptoms. Although it is well established that carbon dioxide (CO2) inhalation triggers anxiety and panic in anxiety disorder patients, the underlying mechanisms are not known. This proposal models CO2- evoked anxiety and panic in mice and suggests that understanding CO2-sensitivity has broad implications, including novel molecular pathways underlying anxiety disorders and new treatment targets
Project start date: 2009-04-16
Project end date: 2014-02-28