173 results on '"Harrison NL"'
Search Results
2. SITES FOR ISOFLURANE ACTION ON INHIBITORY AMINO ACID RECEPTORS REVEALED BY MUTAGENESIS?
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Harrison, NL, primary, Mihic, SJ, additional, Ye, Q, additional, Wick, M, additional, Krasowski, MD, additional, Finn, SE, additional, and Harris, RA, additional
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- 1998
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3. Alcohol-induced tolerance and physical dependence in mice with ethanol insensitive alpha1 GABA A receptors.
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Werner DF, Swihart AR, Ferguson C, Lariviere WR, Harrison NL, and Homanics GE
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- 2009
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4. Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor alpha 4 subunit knockout mice.
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Chandra D, Werner DF, Liang J, Suryanarayanan A, Harrison NL, Spigelman I, Olsen RW, and Homanics GE
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- 2008
5. Voltage-dependent calcium channels regulate melatonin output from cultured chick pineal cells
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Harrison, NL, primary and Zatz, M, additional
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- 1989
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6. A steroid anesthetic prolongs inhibitory postsynaptic currents in cultured rat hippocampal neurons
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Harrison, NL, primary, Vicini, S, additional, and Barker, JL, additional
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- 1987
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7. A novel hyperekplexia-causing mutation in the pre-transmembrane segment 1 of the human glycine receptor alpha1 subunit reduces membrane expression and impairs gating by agonists
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James R. Trudell, Patrizia Stefanoni, Giulia Bellini, Pasqualina Castaldo, Francesco Miceli, Lucio Annunziato, Emanuele Miraglia del Giudice, Antonio Pascotto, Giangennaro Coppola, Maurizio Taglialatela, Neil L. Harrison, Castaldo, P, Stefanoni, P, Miceli, F, Coppola, G, MIRAGLIA DEL GIUDICE, Emanuele, Bellini, Giulia, Pascotto, Antonio, Trudell, Jr, Harrison, Nl, Annunziato, L, Taglialatela, M., Castaldo, Pasqualina, Miceli, Francesco, Miraglia Del Giudice, G, Bellini, E, Pascotto, A, Annunziato, Lucio, and Taglialatela, Maurizio
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Agonist ,Models, Molecular ,medicine.medical_specialty ,Reflex, Startle ,medicine.drug_class ,Mutant ,Gating ,Biology ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Receptors, Glycine ,Internal medicine ,medicine ,Humans ,Hyperekplexia ,neurotransmission ,Receptor ,Molecular Biology ,Glycine receptor ,Brain Diseases ,Cell Biology ,Strychnine ,Molecular biology ,Endocrinology ,chemistry ,hyperekplexia ,Glycine ,Mutation ,human glycine receptor alpha1 ,medicine.symptom ,Ion Channel Gating - Abstract
In this study, we have compared the functional consequences of three mutations (R218Q, V260M, and Q266H) in the alpha(1) subunit of the glycine receptor (GlyRA1) causing hyperekplexia, an inherited neurological channelopathy. In HEK-293 cells, the agonist EC(50s) for glycine-activated Cl(-) currents were increased from 26 microm in wtGlyRA1, to 5747, 135, and 129 microm in R218Q, V260M, and Q266H GlyRA1 channels, respectively. Cl(-) currents elicited by beta-alanine and taurine, which behave as agonists at wtGlyRA1, were decreased in V260M and Q266H mutant receptors and virtually abolished in GlyRA1 R218Q receptors. Gly-gated Cl(-) currents were similarly antagonized by low concentrations of strychnine in both wild-type (wt) and R218Q GlyRA1 channels, suggesting that the Arg-218 residue plays a crucial role in GlyRA1 channel gating, with only minor effects on the agonist/antagonist binding site, a hypothesis supported by our molecular model of the GlyRA1 subunit. The R218Q mutation, but not the V260M or the Q266H mutation, caused a marked decrease of receptor subunit expression both in total cell lysates and in isolated plasma membrane proteins. This decreased expression does not seem to explain the reduced agonist sensitivity of GlyRA1 R218Q channels since no difference in the apparent sensitivity to glycine or taurine was observed when wtGlyRA1 receptors were expressed at levels comparable with those of R218Q mutant receptors. In conclusion, multiple mechanisms may explain the dramatic decrease in GlyR function caused by the R218Q mutation, possibly providing the molecular basis for its association with a more severe clinical phenotype.
- Published
- 2004
8. Ketamine Potentiates AMPA Receptor-mediated Activity in the Somatosensory Cortex.
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Yasin B, Williams DJ, Troyas C, Harrison NL, Makinson CD, and García PS
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- Animals, Humans, Ketamine pharmacology, Somatosensory Cortex drug effects, Somatosensory Cortex metabolism, Receptors, AMPA drug effects, Receptors, AMPA metabolism
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- 2024
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9. Letter to the editor RE: Management of Anterior Urethral Stricture: A survey of Contemporary Practice of Iranian Urologists.
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Harrison NL, Omar AM, and Floyd Jr MS
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- Humans, Iran, Practice Patterns, Physicians' statistics & numerical data, Urology, Male, Urethral Stricture surgery
- Abstract
We read with interest the recent paper by Hosseini et al detailing the management practice of Iranian Urologists towards the management of anterior urethral stricture disease. Please find our letter to the editor regarding this.
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- 2024
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10. Is Stent on a String the New Gold Standard for Postureteroscopy Ureteral Drainage? Evidence from a Systematic Review.
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Harrison NL, Hughes C, and Somani BK
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- Adult, Humans, Child, Ureteroscopy methods, Pain etiology, Drainage adverse effects, Stents adverse effects, Treatment Outcome, Ureteral Calculi complications, Ureter surgery
- Abstract
Introduction: Ureteral stents are widely used throughout urologic surgery, most commonly following ureteroscope (URS) procedures. This systematic review aims to assess the current evidence concerning stent on string (SOS) placed after URS and compare it with stents without strings (SWOSs). Methods: A systematic review was conducted on several databases using the preferred reporting items for systematic review and meta-analysis (PRISMA) methodology for studies in English language, for patients of all age groups, who had an SOS after URS for stone disease. Results: Of 1210 records identified, a total of 22 studies (20 adult and 2 pediatric studies) were included, with a total of 8382 patients. Of these, 3427 (40.9%) had SOSs inserted and 434 (11%) were in the pediatric age group. Our results show that SOS provides several advantages, and compared with SWOS, they were in situ for less time, with no difference in complications such as urinary tract infection or urinary symptoms. Furthermore, significant cost savings, less pain on removal, and high rates of safe home removal were reported in SOS, with >90% patients reporting that they would be happy to remove their SOSs at home. However, a small risk of stent dislodgment must be considered when making decisions regarding SOS placement after URS. Conclusion: SOS provides an excellent option after URS, especially in those patients with no intraoperative complication, and their placement is done as a routine insertion based on surgeon preference. These stents reduce dwell time, pain, cost, risks, and suffering involved from prolonged stenting, and majority of patients are happy to remove it themselves at home. Although their use seems to be still restricted in the current endourology practices, they are likely to become the new gold standard for routine URS in future, with more shared decision making and patient-reported outcome measures coming into the mainstream.
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- 2024
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11. Endogenous currents in HEK 293 cells are inhibited by memantine.
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Harrison NL, Abbott GW, McClenaghan C, Nichols CG, and Cabrera-Garcia D
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- Humans, HEK293 Cells, Memantine pharmacology, Receptors, N-Methyl-D-Aspartate
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- 2023
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12. Haemorrhagic cholecystitis in a young patient, complicated by gallbladder perforation and choledocholithiasis.
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Harrison NL, Hepworth-Lloyd F, Briggs P, and Melling J
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- Female, Humans, Gallbladder diagnostic imaging, Hemorrhage complications, Choledocholithiasis complications, Choledocholithiasis diagnostic imaging, Choledocholithiasis surgery, Cholecystitis complications, Cholecystitis surgery, Gallbladder Diseases complications
- Abstract
Haemorrhagic cholecystitis is a rare condition associated with a high risk of morbidity and mortality. Its pathophysiology is thought to be due to gallbladder wall erosion and infarction secondary to inflammation, which subsequently leads to haemorrhage into the gallbladder lumen or the peritoneal cavity. There is no current official guidance on optimal management of this condition. We describe a case of a female patient in her 40s who presented with right upper quadrant pain, followed by haematemesis. After CT scan, a diagnosis of haemorrhagic cholecystitis was made and initially managed conservatively. In this case, haemorrhagic cholecystitis was later complicated by gallbladder perforation and choledocholithiasis. Definitive management was with emergency open cholecystectomy. We believe this to be the first reported case of haemorrhagic cholecystitis complicated by gallbladder perforation and choledocholithiasis. This report highlights the need for early definitive management of haemorrhagic cholecystitis to prevent subsequent complications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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13. Small bowel obstruction secondary to phytobezoar in a patient with myotonic dystrophy.
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Harrison NL, Santoro G, Ellerby N, and Samad A
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- Humans, Ileum, Intestine, Small diagnostic imaging, Male, Adult, Bezoars complications, Bezoars diagnostic imaging, Bezoars surgery, Intestinal Obstruction diagnostic imaging, Intestinal Obstruction etiology, Intestinal Obstruction surgery, Myotonic Dystrophy complications
- Abstract
A male patient in his 30s, with myotonic dystrophy (DM), presented to the emergency department with abdominal pain and vomiting. CT imaging revealed a soft tissue lesion in the terminal ileum causing small bowel obstruction (SBO). The patient underwent diagnostic laparoscopy which allowed identification and removal of the obstructing lesion. This was in the form of an intact, undigested potato, a phytobezoar. Bezoars are collections of undigested material found in the gastrointestinal (GI) tract, a phytobezoar is composed of plant material and is the most common form of bezoar. DM is a multisystem disorder characterised by skeletal muscle weakness, however it often presents with GI symptoms and the muscles of mastication are often affected. DM is a known risk factor for bezoar formation and should be considered as an important differential in DM patients presenting with SBO., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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14. Commentary on "An assessment of urethral radiation exposure in the treatment of endometrial and rectal cancers".
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Harrison NL and Abdelrahman A
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- Humans, Urethra, Rectal Neoplasms radiotherapy, Radiation Exposure
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- 2023
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15. Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients.
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Cabrera-Garcia D, Miltiades A, Yim P, Parsons S, Elisman K, Mansouri MT, Wagener G, and Harrison NL
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- Humans, von Willebrand Factor, Tissue Plasminogen Activator, Interleukin-1 Receptor-Like 1 Protein, Fibrinolysis, Biomarkers, Fibrin, COVID-19 complications, Thrombosis etiology, Blood Coagulation Disorders etiology, Thrombophilia complications
- Abstract
Severe coronavirus disease-19 (COVID-19) has been associated with fibrin-mediated hypercoagulability and thromboembolic complications. To evaluate potential biomarkers of coagulopathy and disease severity in COVID-19, we measured plasma levels of eight biomarkers potentially associated with coagulation, fibrinolysis, and platelet function in 43 controls and 63 COVID-19 patients, including 47 patients admitted to the intensive care unit (ICU) and 16 non-ICU patients. COVID-19 patients showed significantly elevated levels of fibrinogen, tissue plasminogen activator (t-PA), and its inhibitor plasminogen activation inhibitor 1 (PAI-1), as well as ST2 (the receptor for interleukin-33) and von Willebrand factor (vWF) compared to the control group. We found that higher levels of t-PA, ST2, and vWF at the time of admission were associated with lower survival rates, and that thrombotic events were more frequent in patients with initial higher levels of vWF. These results support a predictive role of specific biomarkers such as t-PA and vWF in the pathophysiology of COVID-19. The data provide support for the case that hypercoagulability in COVID-19 is fibrin-mediated, but also highlights the important role that vWF may play in the genesis of thromboses in the pathophysiology of COVID-19. Interventions designed to enhance fibrinolysis might prove to be useful adjuncts in the treatment of coagulopathy in a subset of COVID-19 patients., (© 2022. Japanese Society of Hematology.)
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- 2022
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16. Reply to Garry: The origin of SARS-CoV-2 remains unresolved.
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Harrison NL and Sachs JD
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- Humans, SARS-CoV-2, COVID-19
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- 2022
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17. How many SARS-CoV-2 "viroporins" are really ion channels?
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Harrison NL, Abbott GW, Gentzsch M, Aleksandrov A, Moroni A, Thiel G, Grant S, Nichols CG, Lester HA, Hartel A, Shepard K, Garcia DC, and Yazawa M
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- Humans, Ion Channels, SARS-CoV-2, Viral Proteins metabolism, COVID-19, Viroporin Proteins
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- 2022
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18. A call for an independent inquiry into the origin of the SARS-CoV-2 virus.
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Harrison NL and Sachs JD
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- Animals, China, Chiroptera, Genome, Viral, Humans, COVID-19 transmission, COVID-19 virology, Communicable Diseases, Emerging virology, SARS-CoV-2 genetics, SARS-CoV-2 isolation & purification, Sequence Analysis, RNA, Truth Disclosure
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- 2022
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19. Insights into Fibrinogen-Mediated COVID-19 Hypercoagubility in Critically Ill Patients.
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Miltiades A, Houck PJ, Monteleone M, Harrison NL, Cabrera-Garcia D, Roh D, and Wagener G
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- Critical Illness, Fibrinogen, Fibrinolysis, Humans, SARS-CoV-2, COVID-19, Tissue Plasminogen Activator
- Abstract
Coronavirus disease-2019 (COVID-19) is associated with hypercoagulability that may cause thromobembolic complications. We describe our recent studies investigating the mechanisms of hypercoagulability in patients with severe COVID-19 requiring mechanical ventilation during the COVID-19 crisis in New York City in spring 2020. Using rotational thombelastometry we found that almost all patients with severe COVID-19 had signs of hypercoagulability compared with non-COVID-19 controls. Specifically, the maximal clot firmness in the fibrin-based extrinsically activated test was almost twice the upper limit of normal in COVID patients, indicating a fibrin-mediated cause for hypercoagulability. To better understand the mechanism of this hypercoagulability we measured the components of the fibrinolytic pathways. Fibrinogen, tissue plasminogen activator and plasminogen activator inhibitor-1, but not plasminogen levels were elevated in patients with severe COVID-19. Our studies indicate that hypercoagulability in COVID-19 may be because of decreased fibrinolysis resulting from inhibition of plasmin through high levels of plasminogen activator inhibitor-1. Clinicians creating treatment protocols for anticoagulation in critically ill COVID-19 patients should consider these potential mechanisms of hypercoaguability., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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20. The envelope protein of SARS-CoV-2 increases intra-Golgi pH and forms a cation channel that is regulated by pH.
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Cabrera-Garcia D, Bekdash R, Abbott GW, Yazawa M, and Harrison NL
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- Animals, Cations, HEK293 Cells, Humans, Hydrogen-Ion Concentration, COVID-19, SARS-CoV-2
- Abstract
Key Points: We report a novel method for the transient expression of SARS-CoV-2 envelope (E) protein in intracellular organelles and the plasma membrane of mammalian cells and Xenopus oocytes. Intracellular expression of SARS-CoV-2 E protein increases intra-Golgi pH. By targeting the SARS-CoV-2 E protein to the plasma membrane, we show that it forms a cation channel, viroporin, that is modulated by changes of pH. This method for studying the activity of viroporins may facilitate screening for new antiviral drugs to identify novel treatments for COVID-19., Abstract: The envelope (E) protein of coronaviruses such as SARS-CoV-1 is proposed to form an ion channel or viroporin that participates in viral propagation and pathogenesis. Here we developed a technique to study the E protein of SARS-CoV-2 in mammalian cells by directed targeting using a carboxyl-terminal fluorescent protein tag, mKate2. The wild-type SARS-CoV-2 E protein can be trafficked to intracellular organelles, notably the endoplasmic reticulum-Golgi intermediate complex, where its expression increases pH inside the organelle. We also succeeded in targeting SARS-CoV-2 E to the plasma membrane, which enabled biophysical analysis using whole-cell patch clamp recording in a mammalian cell line, HEK 293 cells, and two-electrode voltage clamp electrophysiology in Xenopus oocytes. The results suggest that the E protein forms an ion channel that is permeable to monovalent cations such as Na
+ , Cs+ and K+ . The E current is nearly time- and voltage-independent when E protein is expressed in mammalian cells, and is modulated by changes of pH. At pH 6.0 and 7.4, the E protein current is activated, whereas at pH 8.0 and 9.0, the amplitude of E protein current is reduced, and in oocytes the inward E current fades at pH 9 in a time- and voltage-dependent manner. Using this directed targeting method and electrophysiological recordings, potential inhibitors of the E protein can be screened and subsequently investigated for antiviral activity against SARS-CoV-2 in vitro and possible efficacy in treating COVID-19., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)- Published
- 2021
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21. Alcohol reduces the activity of somatostatin interneurons in the mouse prefrontal cortex: A neural basis for its disinhibitory effect?
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Li M, Cabrera-Garcia D, Salling MC, Au E, Yang G, and Harrison NL
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- Action Potentials, Animals, Calcium metabolism, Interneurons drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Prefrontal Cortex drug effects, Pyramidal Cells drug effects, Ethanol pharmacology, Interneurons physiology, Neural Inhibition physiology, Prefrontal Cortex physiology, Pyramidal Cells physiology, Somatostatin
- Abstract
The prefrontal cortex (PFC) is involved in executive ("top-down") control of behavior and its function is especially susceptible to the effects of alcohol, leading to behavioral disinhibition that is associated with alterations in decision making, response inhibition, social anxiety and working memory. The circuitry of the PFC involves a complex interplay between pyramidal neurons (PNs) and several subclasses of inhibitory interneurons (INs), including somatostatin (SST)-expressing INs. Using in vivo calcium imaging, we showed that alcohol dose-dependently altered network activity in layers 2/3 of the prelimbic subregion of the mouse PFC. Low doses of alcohol (1 g/kg, intraperitoneal, i.p.) caused moderate activation of SST INs and weak inhibition of PNs. At moderate to high doses, alcohol (2-3 g/kg) strongly inhibited the activity of SST INs in vivo, and this effect may result in disinhibition, as the activity of a subpopulation of PNs was simultaneously enhanced. In contrast, recordings in brain slices using ex vivo electrophysiology revealed no direct effect of alcohol on the excitability of either SST INs or PNs over a range of concentrations (20 and 50 mM) consistent with the blood alcohol levels reached in the in vivo experiments. This dose-dependent effect of alcohol on SST INs in vivo may reveal a neural basis for the disinhibitory effect of alcohol in the PFC mediated by other neurons within or external to the PFC circuitry., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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22. Diagnostic delay in axial spondyloarthritis: a systematic review and meta-analysis.
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Zhao SS, Pittam B, Harrison NL, Ahmed AE, Goodson NJ, and Hughes DM
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- Delayed Diagnosis, Female, Humans, Male, Arthritis, Psoriatic diagnosis, Spondylarthritis diagnosis, Spondylitis, Ankylosing diagnosis
- Abstract
Background: Delay to diagnosis in axial SpA (axSpA) is longer than in many other rheumatic diseases. Prolonged delay is associate with poorer outcomes, including functional impairment and quality of life. Our aims were to describe global variation in delay to diagnosis, factors associated with delay, and delay compared with PsA., Methods: We searched MEDLINE, PubMed, Embase and Web of Science using a predefined protocol. Diagnostic delay was defined as years between the age at symptom onset and at diagnosis. We pooled the mean delay using random effects inverse variance meta-analysis. We examined variations in pooled estimates using prespecified subgroup analyses and sources of heterogeneity using meta-regression., Results: A total of 64 studies reported the mean diagnostic delay in axSpA patients. The pooled mean delay was 6.7 years (95% CI 6.2, 7.2) with high levels of heterogeneity. Delay to diagnosis did not improve over time when stratifying results by year of publication. Studies from high-income countries (defined by the World Bank) reported longer delays than those from middle-income countries. Factors consistently reported to be associated with longer delays were lower education levels, younger age at symptom onset and absence of extra-articular manifestations (EAMs). The pooled estimate for diagnostic delay from 8 PsA studies was significantly shorter, at 2.6 years (95% CI 1.6, 3.6)., Conclusion: For axSpA patients, delay to diagnosis remains unacceptably prolonged in many parts of the world. Patient factors (e.g. education) and disease presentation (onset age and EAMs) should inform campaigns to improve delay., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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23. Constitutive Genetic Deletion of Hcn1 Increases Alcohol Preference during Adolescence.
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Salling MC and Harrison NL
- Abstract
The hyperpolarization-activated cyclic nucleotide-gated channel (HCN), which underlies the hyperpolarization-activated cation current (I
h ), has diverse roles in regulating neuronal excitability across cell types and brain regions. Recently, HCN channels have been implicated in preclinical models of substance abuse including alcohol. In the prefrontal cortex of rodents, HCN expression and Ih magnitude are developmentally regulated during adolescence and may be vulnerable to alcohol's effects. In mice, binge alcohol consumption during the adolescent period results in a sustained reduction in Ih that coincides with increased alcohol consumption in adulthood, yet the direct role HCN channels have on alcohol consumption are unknown. Here, we show that the genetic deletion of Hcn1 causes an increase in alcohol preference on intermittent 2-bottle choice task in homozygous null (HCN1-/- ) male mice compared to wild-type littermates without affecting saccharine or quinine preference. The targeted viral deletion of HCN1 in pyramidal neurons of the medial prefrontal cortex resulted in a gradual loss of Hcn1 expression and a reduction in Ih magnitude during adolescence, however, this did not significantly affect alcohol consumption or preference. We conclude that while HCN1 regulates alcohol preference, the genetic deletion of Hcn1 in the medial prefrontal cortex does not appear to be the locus for this effect.- Published
- 2020
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24. Prevalence and impact of comorbidities in axial spondyloarthritis: systematic review and meta-analysis.
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Zhao SS, Robertson S, Reich T, Harrison NL, Moots RJ, and Goodson NJ
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- Comorbidity, Humans, Hyperlipidemias epidemiology, Hypertension epidemiology, Obesity epidemiology, Prevalence, Spondylarthritis epidemiology
- Abstract
Objectives: Comorbidities are common in people with axial spondyloarthritis (axSpA). In this systematic review and meta-analysis, we aimed to: (i) describe the prevalence of commonly reported comorbidities, (ii) compare comorbidities between axSpA and control populations, and (iii) examine the impact of comorbidity burden on axSpA outcomes., Methods: We systematically searched Medline, PubMed, Scopus and Web of Science using a predefined protocol in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We excluded studies of only one comorbid condition or a few closely related diseases within one organ system. Where possible, meta-analysis was performed using random-effects models., Results: A total of 40 studies were included for analysis. 36 studies reported prevalence of comorbidities, amounting to a combined sample size of 119 427 patients. The number of comorbidities studied ranged from 3 to 43. The most prevalent individual comorbidities were hypertension (pooled prevalence 23%), hyperlipidaemia (17%) and obesity (14%). Eleven studies consistently showed higher prevalence of comorbidities in axSpA than controls, particularly large differences were seen for depression [pooled odds ratio (OR) 1.80] and heart failure (OR 1.84). Comorbidities (total number of and individual conditions) were also associated with axSpA disease activity, functional impairment, quality of life, work productivity and mortality., Conclusions: Comorbidities are common in axSpA, particularly cardiovascular diseases and risk factors. Most comorbidities were more prevalent in axSpA patients than in control populations. Overall comorbidity burden, and many individual conditions, were associated with axSpA outcomes including worse disease severity, work productivity and mortality., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
- Published
- 2020
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25. Prevalence of extra-articular manifestations in psoriatic arthritis: a systematic review and meta-analysis.
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Pittam B, Gupta S, Harrison NL, Robertson S, Hughes DM, and Zhao SS
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- Adult, Aged, Bone Diseases etiology, Enthesopathy etiology, Female, Fingers pathology, Humans, Inflammatory Bowel Diseases etiology, Male, Middle Aged, Nail Diseases etiology, Prevalence, Uveitis etiology, Arthritis, Psoriatic complications, Bone Diseases epidemiology, Enthesopathy epidemiology, Inflammatory Bowel Diseases epidemiology, Nail Diseases epidemiology, Uveitis epidemiology
- Abstract
Objective: To describe the prevalence of extra-articular manifestations-enthesitis, dactylitis, nail disease, uveitis and IBD-in PsA, and their impact on longitudinal disease outcomes., Methods: We searched Medline, PubMed, Scopus and Web of Science using a predefined protocol in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies using imaging to define extra-articular manifestations (EAMs) were excluded. Where possible, we performed meta-analyses of prevalence estimates, reported as percentages (95% CI). Heterogeneity (I2 statistic) was examined according to study characteristics., Results: We identified 65 studies amounting to a total of 163 299 PsA patients. Enthesitis was assessed in 29 studies with an average prevalence of 30% (95% CI: 24%, 38%). Dactylitis was reported in 35 studies with an average prevalence of 25% (95% CI: 20%, 31%). Nail disease was present in 60% (95% CI: 52%, 68%) across 26 studies, but definitions were often unclear. Uveitis (3.2%; 95% CI: 1.9%, 5.3%) and IBD (3.3%; 95% CI: 1.5%, 7.1%) were less common. Heterogeneity was high (>95%) in all meta-analyses, but could not be explained by study characteristics. No studies examined the impact of EAMs on longitudinal disease outcomes, except that dactylitis increases radiographic progression., Conclusion: Enthesitis, dactylitis and nail disease are highly prevalent in PsA, but not uveitis and IBD. EAM patterns differ from axial SpA despite their shared disease mechanisms, which may help further understand differences between spondyloarthritides. More studies are needed on the impact of EAMs on disease outcomes such as response to treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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26. Differential Synaptic Dynamics and Circuit Connectivity of Hippocampal and Thalamic Inputs to the Prefrontal Cortex.
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Canetta S, Teboul E, Holt E, Bolkan SS, Padilla-Coreano N, Gordon JA, Harrison NL, and Kellendonk C
- Abstract
The medial prefrontal cortex (mPFC) integrates inputs from multiple subcortical regions including the mediodorsal nucleus of the thalamus (MD) and the ventral hippocampus (vHPC). How the mPFC differentially processes these inputs is not known. One possibility is that these two inputs target discreet populations of mPFC cells. Alternatively, individual prefrontal cells could receive convergent inputs but distinguish between both inputs based on synaptic differences, such as communication frequency. To address this, we utilized a dual wavelength optogenetic approach to stimulate MD and vHPC inputs onto single, genetically defined mPFC neuronal subtypes. Specifically, we compared the convergence and synaptic dynamics of both inputs onto mPFC pyramidal cells, and parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-expressing interneurons. We found that all individual pyramidal neurons in layer 2/3 of the mPFC receive convergent input from both MD and vHPC. In contrast, PV neurons receive input biased from the MD, while VIP cells receive input biased from the vHPC. Independent of the target, MD inputs transferred information more reliably at higher frequencies (20 Hz) than vHPC inputs. Thus, MD and vHPC projections converge functionally onto mPFC pyramidal cells, but both inputs are distinguished by frequency-dependent synaptic dynamics and preferential engagement of discreet interneuron populations., (© The Author(s) 2020. Published by Oxford University Press.)
- Published
- 2020
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27. The quality of assessments for childhood psychopathology within a regional medical center.
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Sattler AF, Leffler JM, Harrison NL, Bieber ED, Kosmach JJ, Sim LA, and Whiteside SPH
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- Adolescent, Attention Deficit Disorder with Hyperactivity diagnosis, Child, Female, Humans, Male, Mood Disorders diagnosis, Delivery of Health Care, Integrated statistics & numerical data, Evidence-Based Practice statistics & numerical data, Interview, Psychological, Mental Disorders diagnosis, Mental Health Services statistics & numerical data, Quality of Health Care statistics & numerical data, Self Report statistics & numerical data
- Abstract
Accurate assessment is essential to implementing effective mental health treatment; however, little research has explored child clinicians' assessment practices in applied settings. The current study thus examines practitioners' use of evidence-based assessment (EBA) instruments (i.e., self-report measures and structured interviews), specificity of identified diagnoses (i.e., use of specific diagnostic labels vs. nonstandardized labels, not otherwise specified [NOS] diagnoses, and adjustment disorder diagnoses), and documentation of Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev., DSM-IV-TR, American Psychiatric Association, 2000) criteria. Use of these practices was evaluated via analysis of documentation contained within a regional medical center's medical records. This analysis was limited to 2,499 session notes from patient appointments associated with psychiatric disorders newly diagnosed during 2013. In total, session notes were linked to 694 children aged 7 to 17. Results indicated that EBA use was low overall, although self-report measures were utilized relatively frequently versus structured interviews. Diagnostic specificity was also low overall and clinicians rarely documented full diagnostic criteria; however, EBA use was associated with increased diagnostic specificity. Further, clinicians practicing in psychological, psychiatric, and primary care settings were more likely to use self-report measures as compared to those practicing in an integrated behavioral health social work setting. In addition, structured interviews were most likely to be utilized by clinicians practicing in a psychological services setting. Finally, clinicians were more likely to use self-report measures when the identified primary concern was a mood disorder or attention-deficit/hyperactivity disorder (ADHD). Based on these results, we provide suggestions and references to resources for clinicians seeking to improve the quality of their assessments via implementation of EBA. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
- Published
- 2019
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28. Alcohol Consumption during Adolescence in a Mouse Model of Binge Drinking Alters the Intrinsic Excitability and Function of the Prefrontal Cortex through a Reduction in the Hyperpolarization-Activated Cation Current.
- Author
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Salling MC, Skelly MJ, Avegno E, Regan S, Zeric T, Nichols E, and Harrison NL
- Subjects
- Action Potentials drug effects, Animals, Disease Models, Animal, Male, Memory, Short-Term drug effects, Mice, Mice, Inbred C57BL, Prefrontal Cortex physiopathology, Binge Drinking physiopathology, Central Nervous System Depressants toxicity, Ethanol toxicity, Prefrontal Cortex drug effects, Pyramidal Cells drug effects
- Abstract
Periodic episodes of excessive alcohol consumption ("binge drinking") occur frequently among adolescents, and early binge drinking is associated with an increased risk of alcohol use disorders later in life. The PFC undergoes significant development during adolescence and hence may be especially susceptible to the effects of binge drinking. In humans and in animal models, adolescent alcohol exposure is known to alter PFC neuronal activity and produce deficits in PFC-dependent behaviors, such as decision making, response inhibition, and working memory. Using a voluntary intermittent access to alcohol (IA EtOH) procedure in male mice, we demonstrate that binge-level alcohol consumption during adolescence leads to altered drinking patterns and working memory deficits in young adulthood, two outcomes that suggest medial PFC dysfunction. We recorded from pyramidal neurons (PNs) in the prelimbic subregion of the medial PFC in slices obtained from mice that had IA EtOH and found that they display altered excitability, including a hyperpolarization of the resting membrane potential and reductions in the hyperpolarization-activated cation current (I
h ) and in intrinsic persistent activity (a mode of neuronal firing that is dependent on Ih ). Many of these effects on intrinsic excitability were sustained following abstinence and observed in mice that showed working memory deficits. In addition, we found that resting membrane potential and the Ih -dependent voltage "sag" in prelimbic PFC PNs are developmentally regulated during adolescence, suggesting that adolescent alcohol exposure may compromise PFC function by arresting the normal developmental trajectory of PN intrinsic excitability. SIGNIFICANCE STATEMENT Binge alcohol drinking during adolescence has negative consequences for the function of the developing PFC. Using a mouse model of voluntary binge drinking during adolescence, we found that this behavior leads to working memory deficits and altered drinking behavior in adulthood. In addition, we found that adolescent drinking is associated with specific changes to the intrinsic excitability of pyramidal neurons in the PFC, reducing the ability of these neurons to generate intrinsic persistent activity, a phenomenon thought to be important for working memory. These findings may help explain why human adolescent binge drinkers show performance deficits on tasks mediated by the PFC., (Copyright © 2018 the authors 0270-6474/18/386207-16$15.00/0.)- Published
- 2018
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29. Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain.
- Author
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McCracken LM, Lowes DC, Salling MC, Carreau-Vollmer C, Odean NN, Blednov YA, Betz H, Harris RA, and Harrison NL
- Subjects
- Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Picrotoxin pharmacology, Prosencephalon drug effects, Receptors, Glycine genetics, Glycine metabolism, Glycine Agents pharmacology, Prosencephalon physiology, Receptors, Glycine metabolism, Strychnine pharmacology
- Abstract
Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit ( Glra3
-/- ) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2-/Y animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
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30. Effects of acute alcohol on excitability in the CNS.
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Harrison NL, Skelly MJ, Grosserode EK, Lowes DC, Zeric T, Phister S, and Salling MC
- Subjects
- Animals, Humans, Neurons drug effects, Neurons physiology, Brain drug effects, Brain physiology, Ethanol administration & dosage
- Abstract
Alcohol has many effects on brain function and hence on human behavior, ranging from anxiolytic and mild disinhibitory effects, sedation and motor incoordination, amnesia, emesis, hypnosis and eventually unconsciousness. In recent years a variety of studies have shown that acute and chronic exposure to alcohol can modulate ion channels that regulate excitability. Modulation of intrinsic excitability provides another way in which alcohol can influence neuronal network activity, in addition to its actions on synaptic inputs. In this review, we review "low dose" effects [between 2 and 20 mM EtOH], and "medium dose"; effects [between 20 and 50 mM], by considering in turn each of the many networks and brain regions affected by alcohol, and thereby attempt to integrate in vitro physiological studies in specific brain regions (e.g. amygdala, ventral tegmental area, prefrontal cortex, thalamus, cerebellum etc.) within the context of alcohol's behavioral actions in vivo (e.g. anxiolysis, euphoria, sedation, motor incoordination). This article is part of the Special Issue entitled "Alcoholism"., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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31. GABA A receptor α 4 -subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model.
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Yocum GT, Turner DL, Danielsson J, Barajas MB, Zhang Y, Xu D, Harrison NL, Homanics GE, Farber DL, and Emala CW
- Subjects
- Animals, Asthma immunology, CD4-Positive T-Lymphocytes immunology, Cell Line, Disease Models, Animal, Lung immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pneumonia immunology, Th2 Cells immunology, Asthma genetics, Lung pathology, Pneumonia genetics, Receptors, GABA-A genetics
- Abstract
Emerging evidence indicates that hypnotic anesthetics affect immune function. Many anesthetics potentiate γ-aminobutyric acid A receptor (GABA
A R) activation, and these receptors are expressed on multiple subtypes of immune cells, providing a potential mechanistic link. Like immune cells, airway smooth muscle (ASM) cells also express GABAA Rs, particularly isoforms containing α4 -subunits, and activation of these receptors leads to ASM relaxation. We sought to determine if GABAA R signaling modulates the ASM contractile and inflammatory phenotype of a murine allergic asthma model utilizing GABAA R α4 -subunit global knockout (KO; Gabra40/0 ) mice. Wild-type (WT) and Gabra4 KO mice were sensitized with house dust mite (HDM) antigen or exposed to PBS intranasally 5 days/wk for 3 wk. Ex vivo tracheal rings from HDM-sensitized WT and Gabra4 KO mice exhibited similar magnitudes of acetylcholine-induced contractile force and isoproterenol-induced relaxation ( P = not significant; n = 4). In contrast, in vivo airway resistance (flexiVent) was significantly increased in Gabra4 KO mice ( P < 0.05, n = 8). Moreover, the Gabra4 KO mice demonstrated increased eosinophilic lung infiltration ( P < 0.05; n = 4) and increased markers of lung T-cell activation/memory (CD62L low, CD44 high; P < 0.01, n = 4). In vitro, Gabra4 KO CD4+ cells produced increased cytokines and exhibited increased proliferation after stimulation of the T-cell receptor as compared with WT CD4+ cells. These data suggest that the GABAA R α4 -subunit plays a role in immune cell function during allergic lung sensitization. Thus GABAA R α4 -subunit-specific agonists have the therapeutic potential to treat asthma via two mechanisms: direct ASM relaxation and inhibition of airway inflammation., (Copyright © 2017 the American Physiological Society.)- Published
- 2017
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32. Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area.
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Avegno EM, Salling MC, Borgkvist A, Mrejeru A, Whitebirch AC, Margolis EB, Sulzer D, and Harrison NL
- Subjects
- Action Potentials drug effects, Alcohol Drinking pathology, Alcohol Drinking physiopathology, Animals, Binge Drinking pathology, Choice Behavior, Disease Models, Animal, Dopaminergic Neurons pathology, Dopaminergic Neurons physiology, Dose-Response Relationship, Drug, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Male, Mice, Inbred C57BL, Mice, Transgenic, Substance Withdrawal Syndrome pathology, Substance Withdrawal Syndrome physiopathology, Tyrosine 3-Monooxygenase genetics, Tyrosine 3-Monooxygenase metabolism, Ventral Tegmental Area pathology, Ventral Tegmental Area physiopathology, Volition, Binge Drinking physiopathology, Central Nervous System Depressants toxicity, Dopaminergic Neurons drug effects, Ethanol toxicity, Ventral Tegmental Area drug effects, Ventral Tegmental Area growth & development
- Abstract
Enhanced dopamine (DA) neurotransmission from the ventral tegmental area (VTA) to the ventral striatum is thought to drive drug self-administration and mediate positive reinforcement. We examined neuronal firing rates in slices of mouse midbrain following adolescent binge-like alcohol drinking and find that prior alcohol experience greatly enhanced the sensitivity to excitation by ethanol itself (10-50 mM) in a subset of ventral midbrain DA neurons located in the medial VTA. This enhanced response after drinking was not associated with alterations of firing rate or other measures of intrinsic excitability. In addition, the phenomenon appears to be specific to adolescent drinking, as mice that established a drinking preference only after the onset of adulthood showed no change in alcohol sensitivity. Here we demonstrate not only that drinking during adolescence induces enhanced alcohol sensitivity, but also that this DA neuronal response occurs over a range of alcohol concentrations associated with social drinking in humans., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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33. Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons.
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Canetta S, Bolkan S, Padilla-Coreano N, Song LJ, Sahn R, Harrison NL, Gordon JA, Brown A, and Kellendonk C
- Subjects
- Animals, Disease Models, Animal, Female, GABAergic Neurons metabolism, Humans, Immunity, Active, Inhibition, Psychological, Interneurons metabolism, Male, Memory, Short-Term physiology, Mice, Prefrontal Cortex metabolism, Pregnancy, Prenatal Exposure Delayed Effects, Synaptic Transmission immunology, Synaptic Transmission physiology, gamma-Aminobutyric Acid, Parvalbumins immunology, Parvalbumins metabolism
- Abstract
Abnormalities in prefrontal gamma aminobutyric acid (GABA)ergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders, including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, resulted from a decrease in release probability and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to MIA, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders.
- Published
- 2016
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34. Maternal immune activation does not alter the number of perisomatic parvalbumin-positive boutons in the offspring prefrontal cortex.
- Author
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Canetta S, Bolkan S, Padilla-Coreano N, Song LJ, Sahn R, Harrison NL, Gordon JA, Brown A, and Kellendonk C
- Published
- 2016
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35. Downregulation of Gabra4 expression during alcohol withdrawal is mediated by specific microRNAs in cultured mouse cortical neurons.
- Author
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Bekdash RA and Harrison NL
- Subjects
- Animals, Cells, Cultured, Cerebral Cortex cytology, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Down-Regulation drug effects, Ethanol adverse effects, Male, Mice, Mice, Inbred C57BL, Neurons drug effects, Neurons metabolism, Substance Withdrawal Syndrome genetics, Substance Withdrawal Syndrome metabolism, Cerebral Cortex physiology, MicroRNAs genetics, MicroRNAs metabolism, Receptors, GABA-A biosynthesis, Receptors, GABA-A genetics
- Abstract
Background: Alcohol abuse and dependence are a serious public health problem. A large number of alcohol-regulated genes, (ARGs) are known to be influenced by alcohol use and withdrawal (AW), and recent evidence suggests that neuroadaptation to alcohol may be due in part to epigenetic changes in the expression of ARGs. Gabra4, which encodes the α4 subunit of GABAA receptors (GABAARs), is one of a number of ARGs that show remarkable plasticity in response to alcohol, being rapidly upregulated by acute alcohol exposure. This study addressed the effects of AW on changes in the expression of Gabra4 and related genes that encode other subunits of GABAARs, and the potential regulation of Gabra4 by microRNAs., Methods: We studied gene and microRNAs expression, using RT-PCR and microRNA microarray in cultured cortical neurons treated with alcohol, which was then removed in order to simulate AW in vitro. We also used microRNA mimics or inhibitors, and a promoter-reporter construct carrying the 3'UTR of Gabra4., Results: Eleven hours after removal of alcohol, Gabra4 was downregulated, with a modest increase in the expression of Gabrg2, but no change in the expression of Gabra1, Gabrd, or Gabrb2. microRNA profiling in neurons undergoing AW revealed upregulation in the expression of miR-155, miR-186, miR-24, and miR-375 after 8 h of AW. Transfection with molecular mimics of miR-186, miR-24, or miR-375 also downregulated Gabra4 expression, whereas transfection with the corresponding inhibitors of these microRNAs normalized Gabra4 expression in AW neurons to the level measured in control neurons. Promoter-reporter experiments supported the idea that miR-155, miR-186, miR-24, miR-27b, or miR-375 bind to the 3'UTR of Gabra4 and thereby inhibit protein production., Conclusions: Our data suggest that AW decreases Gabra4 expression, and that this may be mediated in part by the induction of specific microRNAs in cortical neurons during AW.
- Published
- 2015
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36. Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity.
- Author
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Dixon CL, Harrison NL, Lynch JW, and Keramidas A
- Subjects
- Cells, Cultured, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Structure-Activity Relationship, Time Factors, Zolpidem, Eszopiclone pharmacology, Pyridines pharmacology, Receptors, GABA-A metabolism
- Abstract
Background and Purpose: GABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non-benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non-benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of α1β2γ2 GABAA receptors., Experimental Approach: We used rapid ligand application onto macropatches and single-channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing α1β2γ2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism., Key Results: At the single-channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ∼80 nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening., Conclusions and Implications: As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines., (© 2015 The British Pharmacological Society.)
- Published
- 2015
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37. Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does not reduce alcohol consumption.
- Author
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Gallo EF, Salling MC, Feng B, Morón JA, Harrison NL, Javitch JA, and Kellendonk C
- Subjects
- Animals, Conditioning, Operant drug effects, Exploratory Behavior physiology, Locomotion drug effects, Luminescent Proteins genetics, Luminescent Proteins metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways metabolism, Neurons metabolism, Nucleus Accumbens drug effects, Protein Binding drug effects, Protein Binding genetics, Receptors, Dopamine D2 genetics, Up-Regulation drug effects, Alcohol Drinking genetics, Alcohols administration & dosage, Locomotion genetics, Nucleus Accumbens metabolism, Receptors, Dopamine D2 metabolism, Up-Regulation physiology
- Abstract
Brain imaging studies performed in humans have associated low striatal dopamine release and D2R binding with alcohol dependence. Conversely, high striatal D2R binding has been observed in unaffected members of alcoholic families suggesting that high D2R function may protect against alcohol dependence. A possible protective role of increased D2R levels in the striatum is further supported by preclinical studies in non-human primates and rodents. Here, we determined whether there is a causal relationship between D2R levels and alcohol intake. To this end, we upregulated D2R expression levels in the nucleus accumbens of the adult mouse, but selectively restricted the upregulation to the indirect striatal output pathway, which endogenously expresses D2Rs. After overexpression was established, mice were tested in two models of free-choice alcohol drinking: the continuous and intermittent access two-bottle choice models. As anticipated, we found that D2R upregulation leads to hyperactivity in the open field. Contrary to our expectation, D2R upregulation did not reduce alcohol intake during continuous or intermittent access or when alcohol drinking was tested in the context of aversive outcomes. These data argue against a protective role of accumbal indirect pathway D2Rs in alcohol consumption but emphasize their importance in promoting locomotor activity.
- Published
- 2015
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38. A subset of ventral tegmental area dopamine neurons responds to acute ethanol.
- Author
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Mrejeru A, Martí-Prats L, Avegno EM, Harrison NL, and Sulzer D
- Subjects
- Action Potentials drug effects, Animals, Dopaminergic Neurons physiology, Dose-Response Relationship, Drug, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Mice, Inbred C57BL, Mice, Transgenic, Patch-Clamp Techniques, Tissue Culture Techniques, Ventral Tegmental Area physiology, Central Nervous System Depressants pharmacology, Dopaminergic Neurons drug effects, Ethanol pharmacology, Ventral Tegmental Area drug effects
- Abstract
The mechanisms by which alcohol drinking promotes addiction in humans and self-administration in rodents remain obscure, but it is well known that alcohol can enhance dopamine (DA) neurotransmission from neurons of the ventral tegmental area (VTA) and increase DA levels within the nucleus accumbens and prefrontal cortex. We recorded from identified DA neuronal cell bodies within ventral midbrain slices prepared from a transgenic mouse line (TH-GFP) using long-term stable extracellular recordings in a variety of locations and carefully mapped the responses to applied ethanol (EtOH). We identified a subset of DA neurons in the medial VTA located within the rostral linear and interfascicular nuclei that fired spontaneously and exhibited a concentration-dependent increase of firing frequency in response to EtOH, with some neurons responsive to as little as 20mM EtOH. Many of these medial VTA DA neurons were also insensitive to the D2 receptor agonist quinpirole. In contrast, DA neurons in the lateral VTA (located within the parabrachial pigmented and paranigral nuclei) were either unresponsive or responded only to 100mM EtOH. Typically, these lateral VTA DA cells had very slow firing rates, and all exhibited inhibition by quinpirole via D2 "autoreceptors". VTA non-DA cells did not show any significant response to low levels of EtOH. These findings are consistent with evidence for heterogeneity among midbrain DA neurons and provide an anatomical and pharmacological distinction between DA neuron sub-populations that will facilitate future mechanistic studies on the actions of EtOH in the VTA., (Copyright © 2015. Published by Elsevier Ltd.)
- Published
- 2015
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39. Acetaldehyde, not ethanol, impairs myelin formation and viability in primary mouse oligodendrocytes.
- Author
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Coutts DJ and Harrison NL
- Subjects
- Animals, Cell Survival drug effects, Cells, Cultured, Mice, Mice, Inbred C57BL, Oligodendroglia drug effects, Oligodendroglia pathology, Acetaldehyde toxicity, Ethanol toxicity, Myelin Sheath drug effects, Myelin Sheath pathology
- Abstract
Background: Excessive ethanol (EtOH) drinking is associated with white matter loss in the brain at all stages of life. Myelin-forming oligodendrocytes (OLs) are a major component of white matter, but their involvement in EtOH-mediated white matter loss is unclear. Myelination continues throughout the life with highest rates during fetal development and adolescence. However, little is known about the effects of EtOH and its principal metabolite acetaldehyde (ACD) on OLs at the cellular level., Methods: We compared the responses to different concentrations of EtOH or ACD by primary OLs in culture., Results: EtOH did not cause significant cell death at concentrations lower than 120 mM, even after 24 hours. In comparison, ACD was highly lethal at doses above 50 μM. High concentrations of EtOH (120 mM) and ACD (500 μM) for 24 hours did not reduce myelin in mature OLs. Myelin production and OL differentiation were significantly impaired by 7 days exposure to 500 or 50 μM ACD but not 120 mM EtOH., Conclusions: This study shows that OLs are relatively resistant to EtOH, even at a concentration more than 4 times the typical blood EtOH concentrations associated with social drinking (10 to 30 mM). In contrast, OLs are much more sensitive to ACD than EtOH, particularly with long-term exposure. This suggests that part of white matter loss in response to EtOH, especially during high rates of myelin formation, may be due in part to the effects of its principal metabolite ACD., (Copyright © 2015 by the Research Society on Alcoholism.)
- Published
- 2015
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40. Strychnine-sensitive glycine receptors on pyramidal neurons in layers II/III of the mouse prefrontal cortex are tonically activated.
- Author
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Salling MC and Harrison NL
- Subjects
- Animals, GABA Agonists pharmacology, Glycine Agents pharmacology, Inhibitory Postsynaptic Potentials, Male, Mice, Mice, Inbred C57BL, Prefrontal Cortex drug effects, Pyramidal Cells drug effects, Receptors, GABA-A physiology, Strychnine pharmacology, Neural Inhibition, Prefrontal Cortex physiology, Pyramidal Cells physiology, Receptors, Glycine physiology
- Abstract
Processing of signals within the cerebral cortex requires integration of synaptic inputs and a coordination between excitatory and inhibitory neurotransmission. In addition to the classic form of synaptic inhibition, another important mechanism that can regulate neuronal excitability is tonic inhibition via sustained activation of receptors by ambient levels of inhibitory neurotransmitter, usually GABA. The purpose of this study was to determine whether this occurs in layer II/III pyramidal neurons (PNs) in the prelimbic region of the mouse medial prefrontal cortex (mPFC). We found that these neurons respond to exogenous GABA and to the α4δ-containing GABAA receptor (GABA(A)R)-selective agonist gaboxadol, consistent with the presence of extrasynaptic GABA(A)R populations. Spontaneous and miniature synaptic currents were blocked by the GABA(A)R antagonist gabazine and had fast decay kinetics, consistent with typical synaptic GABA(A)Rs. Very few layer II/III neurons showed a baseline current shift in response to gabazine, but almost all showed a current shift (15-25 pA) in response to picrotoxin. In addition to being a noncompetitive antagonist at GABA(A)Rs, picrotoxin also blocks homomeric glycine receptors (GlyRs). Application of the GlyR antagonist strychnine caused a modest but consistent shift (∼15 pA) in membrane current, without affecting spontaneous synaptic events, consistent with the tonic activation of GlyRs. Further investigation showed that these neurons respond in a concentration-dependent manner to glycine and taurine. Inhibition of glycine transporter 1 (GlyT1) with sarcosine resulted in an inward current and an increase of the strychnine-sensitive current. Our data demonstrate the existence of functional GlyRs in layer II/III of the mPFC and a role for these receptors in tonic inhibition that can have an important influence on mPFC excitability and signal processing., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
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41. HSF1 transcriptional activity mediates alcohol induction of Vamp2 expression and GABA release.
- Author
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Varodayan FP and Harrison NL
- Abstract
Many central synapses are highly sensitive to alcohol, and it is now accepted that short-term alterations in synaptic function may lead to longer-term changes in circuit function. The regulation of postsynaptic receptors by alcohol has been well studied, but the mechanisms underlying the effects of alcohol on the presynaptic terminal are relatively unexplored. To identify a pathway by which alcohol regulates neurotransmitter release, we recently investigated the mechanism by which ethanol induces Vamp2, but not Vamp1, in mouse primary cortical cultures. These two genes encode isoforms of synaptobrevin, a vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein required for synaptic vesicle fusion. We found that alcohol activates the transcription factor heat shock factor 1 (HSF1) to induce Vamp2 expression, while Vamp1 mRNA levels remain unaffected. As the Vamp2 gene encodes a SNARE protein, we then investigated whether ethanol exposure and HSF1 transcriptional activity alter neurotransmitter release using electrophysiology. We found that alcohol increased the frequency of γ-aminobutyric acid (GABA)-mediated miniature IPSCs via HSF1, but had no effect on mEPSCs. Overall, these data indicate that alcohol induces HSF1 transcriptional activity to trigger a specific coordinated adaptation in GABAergic presynaptic terminals. This mechanism could explain some of the changes in synaptic function that occur soon after alcohol exposure, and may underlie some of the more enduring effects of chronic alcohol intake on local circuit function.
- Published
- 2013
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42. Anesthetics interfere with axon guidance in developing mouse neocortical neurons in vitro via a γ-aminobutyric acid type A receptor mechanism.
- Author
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Mintz CD, Barrett KM, Smith SC, Benson DL, and Harrison NL
- Subjects
- Analysis of Variance, Anesthesia, General methods, Animals, Brain drug effects, Cells, Cultured, Chemotaxis drug effects, Growth Cones drug effects, In Vitro Techniques, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence methods, Nerve Growth Factors drug effects, Neurogenesis drug effects, Signal Transduction drug effects, Anesthetics, Inhalation pharmacology, Axons drug effects, Isoflurane pharmacology, Neurons drug effects, Receptors, GABA drug effects
- Abstract
Background: The finding that exposure to general anesthetics (GAs) in childhood may increase rates of learning disabilities has raised a concern that anesthetics may interfere with brain development. The generation of neuronal circuits, a complex process in which axons follow guidance cues to dendritic targets, is an unexplored potential target for this type of toxicity., Methods: GA exposures were conducted in developing neocortical neurons in culture and in early postnatal neocortical slices overlaid with fluorescently labeled neurons. Axon targeting, growth cone collapse, and axon branching were measured using quantitative fluorescence microscopy., Results: Isoflurane exposure causes errors in Semaphorin-3A-dependent axon targeting (n = 77 axons) and a disruption of the response of axonal growth cones to Semaphorin-3A (n = 2,358 growth cones). This effect occurs at clinically relevant anesthetic doses of numerous GAs with allosteric activity at γ-aminobutyric acid type A receptors, and it was reproduced with a selective agonist. Isoflurane also inhibits growth cone collapse induced by Netrin-1, but does not interfere branch induction by Netrin-1. Insensitivity to guidance cues caused by isoflurane is seen acutely in growth cones in dissociated culture, and errors in axon targeting in brain slice culture occur at the earliest point at which correct targeting is observed in controls., Conclusions: These results demonstrate a generalized inhibitory effect of GAs on repulsive growth cone guidance in the developing neocortex that may occur via a γ-aminobutyric acid type A receptor mechanism. The finding that GAs interfere with axon guidance, and thus potentially with circuit formation, represents a novel form of anesthesia neurotoxicity in brain development.
- Published
- 2013
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43. Brief alcohol exposure alters transcription in astrocytes via the heat shock pathway.
- Author
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Pignataro L, Varodayan FP, Tannenholz LE, Protiva P, and Harrison NL
- Abstract
Astrocytes are critical for maintaining homeostasis in the central nervous system (CNS), and also participate in the genomic response of the brain to drugs of abuse, including alcohol. In this study, we investigated ethanol regulation of gene expression in astrocytes. A microarray screen revealed that a brief exposure of cortical astrocytes to ethanol increased the expression of a large number of genes. Among the alcohol-responsive genes (ARGs) are glial-specific immune response genes, as well as genes involved in the regulation of transcription, cell proliferation, and differentiation, and genes of the cytoskeleton and extracellular matrix. Genes involved in metabolism were also upregulated by alcohol exposure, including genes associated with oxidoreductase activity, insulin-like growth factor signaling, acetyl-CoA, and lipid metabolism. Previous microarray studies performed on ethanol-treated hepatocyte cultures and mouse liver tissue revealed the induction of almost identical classes of genes to those identified in our microarray experiments, suggesting that alcohol induces similar signaling mechanisms in the brain and liver. We found that acute ethanol exposure activated heat shock factor 1 (HSF1) in astrocytes, as demonstrated by the translocation of this transcription factor to the nucleus and the induction of a family of known HSF1-dependent genes, the heat shock proteins (Hsps). Transfection of a constitutively transcriptionally active Hsf1 construct into astrocytes induced many of the ARGs identified in our microarray study supporting the hypothesis that HSF1 transcriptional activity, as part of the heat shock cascade, may mediate the ethanol induction of these genes. These data indicate that acute ethanol exposure alters gene expression in astrocytes, in part via the activation of HSF1 and the heat shock cascade.
- Published
- 2013
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44. Striatal D2 receptors regulate dendritic morphology of medium spiny neurons via Kir2 channels.
- Author
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Cazorla M, Shegda M, Ramesh B, Harrison NL, and Kellendonk C
- Subjects
- Animals, Corpus Striatum cytology, Corpus Striatum physiology, Dendrites physiology, Down-Regulation physiology, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Neural Inhibition physiology, Neurons classification, Neurons metabolism, Potassium Channels, Inwardly Rectifying antagonists & inhibitors, Receptors, Dopamine D2 metabolism, Corpus Striatum metabolism, Dendrites metabolism, Neurons physiology, Potassium Channels, Inwardly Rectifying physiology, Receptors, Dopamine D2 physiology
- Abstract
Structural plasticity in the adult brain is essential for adaptive behaviors and is thought to contribute to a variety of neurological and psychiatric disorders. Medium spiny neurons of the striatum show a high degree of structural plasticity that is modulated by dopamine through unknown signaling mechanisms. Here, we demonstrate that overexpression of dopamine D2 receptors in medium spiny neurons increases their membrane excitability and decreases the complexity and length of their dendritic arbors. These changes can be reversed in the adult animal after restoring D2 receptors to wild-type levels, demonstrating a remarkable degree of structural plasticity in the adult striatum. Increased excitability and decreased dendritic arborization are associated with downregulation of inward rectifier potassium channels (Kir2.1/2.3). Downregulation of Kir2 function is critical for the neurophysiological and morphological changes in vivo because virally mediated expression of a dominant-negative Kir2 channel is sufficient to recapitulate the changes in D2 transgenic mice. These findings may have important implications for the understanding of basal ganglia disorders, and more specifically schizophrenia, in which excessive activation of striatal D2 receptors has long been hypothesized to be of pathophysiologic significance.
- Published
- 2012
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45. Alcohol induces synaptotagmin 1 expression in neurons via activation of heat shock factor 1.
- Author
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Varodayan FP, Pignataro L, and Harrison NL
- Subjects
- Analysis of Variance, Animals, Cells, Cultured, Cerebral Cortex cytology, Chromosomal Proteins, Non-Histone genetics, Chromosomal Proteins, Non-Histone metabolism, DNA-Binding Proteins genetics, Dose-Response Relationship, Drug, Embryo, Mammalian, Genome, Heat Shock Transcription Factors, Hot Temperature, Mice, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, RNA Interference physiology, RNA, Messenger metabolism, Synaptotagmin I genetics, Transcription Factors genetics, Vesicle-Associated Membrane Protein 1 metabolism, Vesicle-Associated Membrane Protein 2 metabolism, Central Nervous System Depressants pharmacology, DNA-Binding Proteins metabolism, Ethanol pharmacology, Gene Expression Regulation drug effects, Neurons drug effects, Synaptotagmin I metabolism, Transcription Factors metabolism
- Abstract
Many synapses within the central nervous system are sensitive to ethanol. Although alcohol is known to affect the probability of neurotransmitter release in specific brain regions, the effects of alcohol on the underlying synaptic vesicle fusion machinery have been little studied. To identify a potential pathway by which ethanol can regulate neurotransmitter release, we investigated the effects of acute alcohol exposure (1-24 h) on the expression of the gene encoding synaptotagmin 1 (Syt1), a synaptic protein that binds calcium to directly trigger vesicle fusion. Syt1 was identified in a microarray screen as a gene that may be sensitive to alcohol and heat shock. We found that Syt1 mRNA and protein expression are rapidly and robustly up-regulated by ethanol in mouse cortical neurons, and that the distribution of Syt1 protein along neuronal processes is also altered. Syt1 mRNA up-regulation is dependent on the activation of the transcription factor heat shock factor 1 (HSF1). The transfection of a constitutively active Hsf1 construct into neurons stimulates Syt1 transcription, while transfection of Hsf1 small interfering RNA (siRNA) or a constitutively inactive Hsf1 construct into neurons attenuates the induction of Syt1 by ethanol. This suggests that the activation of HSF1 can induce Syt1 expression and that this may be a mechanism by which alcohol regulates neurotransmitter release during brief exposures. Further analysis revealed that a subset of the genes encoding the core synaptic vesicle fusion (soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor; SNARE) proteins share this property of induction by ethanol, suggesting that alcohol may trigger a specific coordinated adaptation in synaptic function. This molecular mechanism could explain some of the changes in synaptic function that occur following alcohol administration and may be an important step in the process of neuronal adaptation to alcohol., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2011
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46. Inhaled anesthetic responses of recombinant receptors and knockin mice harboring α2(S270H/L277A) GABA(A) receptor subunits that are resistant to isoflurane.
- Author
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Werner DF, Swihart A, Rau V, Jia F, Borghese CM, McCracken ML, Iyer S, Fanselow MS, Oh I, Sonner JM, Eger EI 2nd, Harrison NL, Harris RA, and Homanics GE
- Subjects
- Animals, Conditioning, Psychological drug effects, Conditioning, Psychological physiology, Drug Resistance drug effects, Fear drug effects, Fear physiology, Female, Gene Knock-In Techniques, Humans, Mice, Mice, Inbred C57BL, Rats, Receptors, GABA-A genetics, Recombinant Proteins agonists, Recombinant Proteins genetics, Xenopus laevis, gamma-Aminobutyric Acid pharmacology, Anesthetics, Inhalation administration & dosage, Drug Resistance physiology, Isoflurane administration & dosage, Receptors, GABA-A physiology
- Abstract
The mechanism by which the inhaled anesthetic isoflurane produces amnesia and immobility is not understood. Isoflurane modulates GABA(A) receptors (GABA(A)-Rs) in a manner that makes them plausible targets. We asked whether GABA(A)-R α2 subunits contribute to a site of anesthetic action in vivo. Previous studies demonstrated that Ser270 in the second transmembrane domain is involved in the modulation of GABA(A)-Rs by volatile anesthetics and alcohol, either as a binding site or a critical allosteric residue. We engineered GABA(A)-Rs with two mutations in the α2 subunit, changing Ser270 to His and Leu277 to Ala. Recombinant receptors with these mutations demonstrated normal affinity for GABA, but substantially reduced responses to isoflurane. We then produced mutant (knockin) mice in which this mutated subunit replaced the wild-type α2 subunit. The adult mutant mice were overtly normal, although there was evidence of enhanced neonatal mortality and fear conditioning. Electrophysiological recordings from dentate granule neurons in brain slices confirmed the decreased actions of isoflurane on mutant receptors contributing to inhibitory synaptic currents. The loss of righting reflex EC(50) for isoflurane did not differ between genotypes, but time to regain the righting reflex was increased in N(2) generation knockins. This effect was not observed at the N(4) generation. Isoflurane produced immobility (as measured by tail clamp) and amnesia (as measured by fear conditioning) in both wild-type and mutant mice, and potencies (EC(50)) did not differ between the strains for these actions of isoflurane. Thus, immobility or amnesia does not require isoflurane potentiation of the α2 subunit.
- Published
- 2011
- Full Text
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47. Loss of ethanol conditioned taste aversion and motor stimulation in knockin mice with ethanol-insensitive α2-containing GABA(A) receptors.
- Author
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Blednov YA, Borghese CM, McCracken ML, Benavidez JM, Geil CR, Osterndorff-Kahanek E, Werner DF, Iyer S, Swihart A, Harrison NL, Homanics GE, and Harris RA
- Subjects
- Alcohol Drinking genetics, Animals, Avoidance Learning drug effects, Conditioning, Psychological drug effects, Female, Gene Knock-In Techniques, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Motor Activity drug effects, Receptors, GABA-A physiology, Taste drug effects, Xenopus laevis, Avoidance Learning physiology, Conditioning, Psychological physiology, Ethanol administration & dosage, Motor Activity genetics, Receptors, GABA-A genetics, Taste genetics
- Abstract
GABA type A receptors (GABA(A)-Rs) are potential targets of ethanol. However, there are multiple subtypes of this receptor, and, thus far, individual subunits have not been definitively linked with specific ethanol behavioral actions. Interestingly, though, a chromosomal cluster of four GABA(A)-R subunit genes, including α2 (Gabra2), was associated with human alcoholism (Am J Hum Genet 74:705-714, 2004; Pharmacol Biochem Behav 90:95-104, 2008; J Psychiatr Res 42:184-191, 2008). The goal of our study was to determine the role of receptors containing this subunit in alcohol action. We designed an α2 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity in a recombinant expression system. Knockin mice containing this mutant subunit were tested in a range of ethanol behavioral tests. These mutant mice did not develop the typical conditioned taste aversion in response to ethanol and showed complete loss of the motor stimulant effects of ethanol. Conversely, they also demonstrated changes in ethanol intake and preference in multiple tests. The knockin mice showed increased ethanol-induced hypnosis but no difference in anxiolytic effects or recovery from acute ethanol-induced motor incoordination. Overall, these studies demonstrate that the effects of ethanol at GABAergic synapses containing the α2 subunit are important for specific behavioral effects of ethanol that may be relevant to the genetic linkage of this subunit with human alcoholism.
- Published
- 2011
- Full Text
- View/download PDF
48. The activation mechanism of alpha1beta2gamma2S and alpha3beta3gamma2S GABAA receptors.
- Author
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Keramidas A and Harrison NL
- Subjects
- Cell Line, Humans, Ion Channel Gating physiology, Kidney metabolism, Membrane Potentials physiology, Receptors, GABA-A metabolism, gamma-Aminobutyric Acid metabolism
- Abstract
The alpha1beta2gamma2 and alpha3beta3gamma2 are two isoforms of gamma-aminobutyric acid type A (GABAA) receptor that are widely distributed in the brain. Both are found at synapses, for example in the thalamus, where they mediate distinctly different inhibitory postsynaptic current profiles, particularly with respect to decay time. The two isoforms were expressed in HEK293 cells, and single-channel activity was recorded from outside-out patches. The kinetic characteristics of both isoforms were investigated by analyzing single-channel currents over a wide range of GABA concentrations. Alpha1beta2gamma2 channels exhibited briefer active periods than alpha3beta3gamma2 channels over the entire range of agonist concentrations and had lower intraburst open probabilities at subsaturating concentrations. Activation mechanisms were constructed by fitting postulated schemes to data recorded at saturating and subsaturating GABA concentrations simultaneously. Reaction mechanisms were ranked according to log-likelihood values and how accurately they simulated ensemble currents. The highest ranked mechanism for both channels consisted of two sequential binding steps, followed by three conducting and three nonconducting configurations. The equilibrium dissociation constant for GABA at alpha3beta3gamma2 channels was approximately 2.6 microM compared with approximately 19 microM for alpha1beta2gamma2 channels, suggesting that GABA binds to the alpha3beta3gamma2 channels with higher affinity. A notable feature of the mechanism was that two consecutive doubly liganded shut states preceded all three open configurations. The lifetime of the third shut state was briefer for the alpha3beta3gamma2 channels. The longer active periods, higher affinity, and preference for conducting states are consistent with the slower decay of inhibitory currents at synapses that contain alpha3beta3gamma2 channels. The reaction mechanism we describe here may also be appropriate for the analysis of other types of GABAA receptors and provides a framework for rational investigation of the kinetic effects of a variety of therapeutic agents that activate or modulate GABAA receptors and hence influence synaptic and extrasynaptic inhibition in the central nervous system.
- Published
- 2010
- Full Text
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49. The regulation of neuronal gene expression by alcohol.
- Author
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Pignataro L, Varodayan FP, Tannenholz LE, and Harrison NL
- Subjects
- Adaptation, Physiological, Animals, Base Sequence, DNA-Binding Proteins drug effects, Epigenesis, Genetic, Gene Expression Profiling, Humans, Models, Genetic, Neurons metabolism, Oligonucleotide Array Sequence Analysis, Repressor Proteins drug effects, Ethanol pharmacology, Gene Expression Regulation drug effects, Neurons drug effects
- Abstract
In recent years there has been an explosion of interest in how genes regulate alcohol drinking and contribute to alcoholism. This work has been stimulated by the completion of the human and mouse genome projects and the resulting availability of gene microarrays. Most of this work has been performed in drinking animals, and has utilized the extensive genetic variation among different mouse strains. At the same time, a much smaller amount of effort has gone into the in vitro study of the mechanisms underlying the regulation of individual genes by alcohol. These studies at the cellular and sub-cellular level are beginning to reveal the ways in which alcohol can interact with the transcriptional, translational and post-translational events inside the cell. Detailed studies of the promoter regions within several individual alcohol-responsive genes (ARGs) have been performed and this work has uncovered intricate signaling pathways that may be generalized to larger groups of ARGs. In the last few years several distinct ARGs have been identified from 35,000 mouse genes, by both the "top-down" approach (ex vivo gene arrays) and the "bottom-up" methods (in vitro promoter analysis). These divergent methodologies have converged on a surprisingly small number of genes encoding ion channels, receptors, transcription factors and proteins involved in synaptic function and remodeling. In this review we will describe some of the most interesting cellular and microarray work in the field, and will outline specific examples of genes for which the mechanisms of regulation by alcohol are now somewhat understood.
- Published
- 2009
- Full Text
- View/download PDF
50. Extrasynaptic GABAA receptors: form, pharmacology, and function.
- Author
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Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, and Cope DW
- Subjects
- Animals, Biophysical Phenomena drug effects, Biophysical Phenomena physiology, Central Nervous System drug effects, Female, Humans, Male, Neural Inhibition drug effects, Pregnancy, Presynaptic Terminals drug effects, Protein Subunits physiology, Synaptic Transmission drug effects, Synaptic Transmission physiology, gamma-Aminobutyric Acid metabolism, gamma-Aminobutyric Acid pharmacology, Central Nervous System physiology, Neural Inhibition physiology, Presynaptic Terminals metabolism, Receptors, GABA-A physiology
- Abstract
GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABA(A) and GABA(B) receptors. Recently, a novel form of GABA(A) receptor-mediated inhibition, termed "tonic" inhibition, has been described. Whereas synaptic GABA(A) receptors underlie classical "phasic" GABA(A) receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABA(A) receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABA(A) receptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This mini-symposium review highlights ongoing work examining the properties of recombinant and native extrasynaptic GABA(A) receptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABA(A) receptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.
- Published
- 2009
- Full Text
- View/download PDF
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