DOCSLIB.ORG

Α7 Nicotinic Receptor Up-Regulation in Cholinergic Basal Forebrain Neurons in Alzheimer Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Α7 Nicotinic Receptor Up-Regulation in Cholinergic Basal Forebrain Neurons in Alzheimer Disease ORIGINAL CONTRIBUTION ␣7 Nicotinic Receptor Up-regulation in Cholinergic Basal Forebrain Neurons in Alzheimer Disease Scott E. Counts, PhD; Bin He, MD; Shaoli Che, MD, PhD; Milos D. Ikonomovic, MD; Steven T. DeKosky, MD; Stephen D. Ginsberg, PhD; Elliott J. Mufson, PhD Background: Dysfunction of basocortical cholinergic pro- Participants: Participants were members of the Rush jection neurons of the nucleus basalis (NB) correlates with Religious Orders Study cohort. cognitive deficits in Alzheimer disease (AD). Nucleus ba- Main Outcome Measures: Real-time quantitative poly- salis neurons receive cholinergic inputs and express nico- merase chain reaction was performed to validate micro- tinic acetylcholine receptors (nAChRs) and muscarinic array findings. AChRs (mAChRs), which may regulate NB neuron activ- ity in AD. Although alterations in these AChRs occur in Results: Cholinergic NB neurons displayed a statisti- the AD cortex, there is little information detailing whether cally significant up-regulation of ␣7 nAChR messenger defects in nAChR and mAChR gene expression occur in RNA expression in subjects with mild to moderate AD cholinergic NB neurons during disease progression. compared with those with NCI and MCI (PϽ.001). No differences were found for other nAChR and mAChR sub- types across the cohort. Expression levels of ␣7 nAChRs Objective: To determine whether nAChR and mAChR were inversely associated with Global Cognitive Score and gene expression is altered in cholinergic NB neurons dur- with Mini-Mental State Examination performance. ing the progression of AD. Conclusions: Up-regulation of ␣7 nAChRs may signal Design: Individual NB neurons from subjects diag- a compensatory response to maintain basocortical cho- nosed ante mortem as having no cognitive impairment linergic activity during AD progression. Alternatively, pu- ␤ (NCI), mild cognitive impairment (MCI), or mild to mod- tative competitive interactions of this receptor with -amy- loid may provide a pathogenic mechanism for NB erate AD were analyzed by single-cell AChR expression ␣ profiling via custom-designed microarrays. dysfunction. Increasing NB 7 nAChR expression may serve as a marker for the progression of AD. Setting: Academic research. Arch Neurol. 2007;64(12):1771-1776 ORTICAL PROJECTION NEU- nAChRs,9 suggesting that the cholinergic rons of the cholinergic tone of NB projection neurons in the AD Author Affiliations: basal forebrain nucleus ba- brain may be regulated by their expres- Department of Neurological salis (NB) play a key role sion of AChRs. To investigate whether Sciences, Rush University in memory and atten- AChR gene expression is altered during the Medical Center, Chicago, tion1 and undergo selective degeneration in progression of AD, we performed single- Illinois (Drs Counts, He, and C Mufson); Center for Dementia Alzheimer disease (AD) that correlates with cell genetic profiling to generate mAChR Research, Nathan Kline disease duration and degree of cognitive im- and nAChR expression profiles for indi- 2 Institute and Department of pairment. Cholinergic neurotransmis- vidual cholinergic NB neurons microaspi- Psychiatry (Drs Che and sion is mediated by nicotinic acetylcho- rated in tissue samples from individuals Ginsberg), and Department of line receptors (nAChRs) and muscarinic clinically diagnosed ante mortem as hav- Physiology and Neuroscience AChRs (mAChRs) through ligand-gated ing no cognitive impairment (NCI), mild (Dr Ginsberg), New York Ca2ϩ influx and G protein–coupled recep- cognitive impairment (MCI) (a putative University School of Medicine, tor-mediated pathways, respectively.3,4 preclinical AD stage10), or mild to moder- Orangeburg; and Departments Binding of nAChRs is reduced in the AD ate AD. We also examined whether changes of Psychiatry and Neurology 5,6 (Drs Ikonomovic and cortex, indicating a loss of cortical cho- in AChR messenger RNA (mRNA) levels DeKosky), University of linergic activity as the disease progresses. were associated with antemortem cogni- Pittsburgh Medical Center, Intriguingly, NB neurons receive cholin- tive performance or with postmortem neu- Pittsburgh, Pennsylvania. ergic afferents7 and express mAChRs8 and ropathological variables. (REPRINTED) ARCH NEUROL / VOL 64 (NO. 12), DEC 2007 WWW.ARCHNEUROL.COM 1771 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table. Case Demographicsa Clinical Diagnosis Group NCI MCI AD Total Comparison Pairwise Variable (n=12) (n=10) (n=12) (N=34) P Value Comparisonsb Age, y 81.0±9.1 81.9±4.3 84.5±6.9 82.4±7.1 .34 . Male sex 6 (50) 3 (30) 5 (42) 14 (41) .68c ... Education, y 17.5±4.8 18.8±2.3 16.3±4.1 17.6±3.9 .41 . PMI, h 12.4±10.7 7.8±4.7 6.9±3.2 7.4±3.2 .70 . Mini-Mental State Examination score 27.6±1.5 26.6±2.8 14.0±9.7 22.4±8.8 Ͻ.001 (NCI, MCI)ϾAD Global Cognitive Score 0.5±0.3 0.2±0.2 −0.9±0.5 0.0±0.7 Ͻ.001 (NCI, MCI)ϾAD APOE ε4 allele 2 (17) 4 (40) 6 (50) 12 (35) .13c ... Braak score .02 NCIϽ(MCI, AD) 01001 I/II 5 0 1 6 III/IV 6 8 4 18 V/VI 0 2 7 9 National Institute on Aging and Reagan Institute .004 NCIϽAD Working Group diagnosis No 1 0 0 1 ... ... Low 8 3 1 12 ... ... Intermediate 3 7 7 17 ... ... High 0 0 4 4 ... ... Abbreviations: AD, mild to moderate Alzheimer disease; MCI, mild cognitive impairment; NCI, no cognitive impairment; PMI, postmortem interval. a Data are given as mean±SD, number, or as percentages unless otherwise indicated. b Bonferroni-type correction. c Fisher exact test. Kruskal-Wallis test for all other values in this column. METHODS IMMUNOHISTOCHEMISTRY Ribonuclease-free precautions were used throughout the experi- CLINICAL AND PATHOLOGICAL EVALUATION mental procedures. The presence of intact RNA in the tissue sec- tions was confirmed by acridine orange histofluorescence and bio- Details of the annual clinical and neuropsychological evalua- analysis (Agilent, Santa Clara, California).17,18 Tissue sections were tions of the Rush Religious Orders Study cohort have been pub- processed using a monoclonal antibody raised against the hu- lished.11 Cognitive testing was performed under the auspices of man p75 neurotrophin receptor, which co-localizes with approxi- a neuropsychologist, and scores were available within the last year mately 95% of all cholinergic basal forebrain neurons within the prior to death. A board-certified neurologist with expertise in the human NB.19 Tissue sections were incubated for 1 hour in a phos- evaluation of older persons made a clinical diagnosis for each par- phate-buffered saline (pH 7.2) solution containing 0.3% Triton ticipant based on review of all clinical data and physical exami- X-100, 3% normal horse serum, and 2% bovine serum albumin. nation findings. Subjects were categorized as having NCI (n=12), Primary antibody (human p75 neurotrophin receptor, 1:60 000; MCI (n=10), or mild to moderate AD (n=12) (Table). The MCI Neomarkers, Fremont, California) was applied for 4 hours at ap- population was defined as subjects who exhibited impaired neu- proximately 25°C in phosphate-buffered saline containing 0.4% ropsychological test scores but did not meet the clinical criteria Triton X-100, 1% normal horse serum, and 1% bovine serum al- for AD recommended by the Joint Working Group of the Na- bumin. Sections were processed (ABC kit; Vector Laboratories, tional Institute of Neurological and Communicative Disorders and Burlingame, California) and developed with 2.5% nickel II sul- Stroke and the Alzheimer’s Disease and Related Disorders Asso- fate, 0.05% 3,3-diaminobenzidine (Sigma-Aldrich Inc, St Louis, ciation.12 These criteria are compatible with those used by ex- Missouri), and 0.005% hydrogen peroxide.13 Immunostained tis- perts in the field to describe subjects who are not cognitively nor- sue sections were slide mounted but not coverslipped and were mal but do not meet established criteria for dementia.10 None of stored in phosphate buffer at 4°C. the subjects examined reported a history of smoking or cholin- esterase inhibitor therapy on entry into the cohort. At autopsy, brains were removed from the calvarium and SINGLE-CELL MICROASPIRATION, RNA were cut into 0.5-cm-thick slabs using a transparent thermo- AMPLIFICATION, AND ARRAY HYBRIDIZATION plastic brain-cutting apparatus (produced by the University of Illinois, Chicago). The slabs were hemisected, and 1 hemi- Immunopositive neurons from the anterior NB subfield were sphere was immersion fixed in a 4% paraformaldehyde solu- aspirated using a micromanipulator and microcontrolled vacuum tion in 0.1M phosphate buffer (pH 7.2), cryoprotected, and cut source (Eppendorf, Westbury, New York) attached to an in- frozen into 40-µm-thick sections.13 Neuropathological assess- verted microscope (Nikon TE2000; Fryer, Huntley, Illinois).13,20,21 ments were performed by a neuropathologist blinded to clini- RNA amplification from NB neurons was performed using ter- cal diagnosis. Cases were classified based on the National In- minal continuation (TC) RNA amplification methods17,18 (http: stitute on Aging and the Reagan Institute Working Group14 and //cdr.rfmh.org/pages/ginsberglabpage.html). The final ampli- Consortium to Establish a Registry for Alzheimer’s Disease cri- fication step used complementary DNA (cDNA) made from teria,15 as well as by Braak stage.16 Slabs from the opposite hemi- individual neuronal mRNA as a template for in vitro transcrip- sphere were frozen at −80°C. tion in the presence of T7 RNA polymerase and phosphorus P (REPRINTED) ARCH NEUROL / VOL 64 (NO. 12), DEC 2007 WWW.ARCHNEUROL.COM 1772 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 ∗ CHRM1 CHRM2 CHRM3 CHRM4 CHRM5 CHRNA1 CHRNA2 CHRNA3 CHRNA4 CHRNA5 CHRNA6 CHRNA7 CHRNB1 CHRNB2 CHRNB3 CHRNB4 AD MCI NCI 048 Figure 1. Dendrogram illustrating relative expression levels of muscarinic acetylcholine receptors (CHRM1-5) and nicotinic acetylcholine receptors (CHRNA1-7 and CHRNB1-4) within individual nucleus basalis neurons from subjects with mild to moderate Alzheimer disease (AD), mild cognitive impairment (MCI), or no cognitive impairment (NCI).
Load more

Recommended publications
  • Main Hypotheses, Concepts and Theories in the Study of Alzheimer's Disease
    An, et al, Main hypotheses, concepts and theories in the study of Alzheimer’s disease Main hypotheses, concepts and theories in the study of Alzheimer’s disease Yuhui An*, Chao Zhang, Siyu He, Chunxia Yao, Limei Zhang, Qian Zhang Department of Biochemistry and Molecular Biology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450052, China Received September 2, 2008 Abstract The incidence of Alzheimer’s disease (AD) is 25 millions worldwide in 2000 and it is expected to increase to 63 and 114 millions in 2030 and 2050, respectively. Nowadays, such aging disease has caused enormous medical and financial burden to the community, which effective prevention and treatment are urgently needed. In this study, we have reviewed different hypotheses, concepts and theories of AD. These include hypothesis related to the loss of cholinergic neuron, calcium, oxidative imbalance, microtubule instability and amyloid cascade; the concepts about mild cognitive impair- ment and the regulation and interference of original molecule; and the theories of nitric oxide and glutamate neurotoxic- ity. Although genetic tests have existed for the research of AD, they are considered useful only for the small number of families with a history of early-onset illness. Because AD is a genetically heterogeneous disorder, it is classified as familial and sporadic. We hope this review can briefly provide a summary of the general knowledge about sporadic AD, and help to promote the research on AD or related prevention and treatment. [Life Science Journal. 2008; 5(4): 1 – 5] (ISSN: 1097 – 8135). Keywords: Alzheimer’s disease; cognitive impairment; memory loss; hypothesis; conception; theory 1 Introduction Although genetic tests have existed for the research of Alzheimer disease, they are considered useful only for According to a report of world heath organization the small number of families with a history of early-onset (WHO)[1], the incidence of Alzheimer’s disease (AD), a illness.
    [Show full text]
  • Genetics and Molecular Biology, 43, 4, E20190404 (2020) Copyright © Sociedade Brasileira De Genética
    Genetics and Molecular Biology, 43, 4, e20190404 (2020) Copyright © Sociedade Brasileira de Genética. DOI: https://doi.org/10.1590/1678-4685-GMB-2019-0404 Short Communication Human and Medical Genetics Influence of a genetic variant of CHAT gene over the profile of plasma soluble ChAT in Alzheimer disease Patricia Fernanda Rocha-Dias1, Daiane Priscila Simao-Silva2,5, Saritha Suellen Lopes da Silva1, Mauro Roberto Piovezan3, Ricardo Krause M. Souza4, Taher. Darreh-Shori5, Lupe Furtado-Alle1 and Ricardo Lehtonen Rodrigues Souza1 1Universidade Federal do Paraná (UFPR), Centro Politécnico, Programa de Pós-Graduação em Genética, Departamento de Genética, Curitiba, PR, Brazil. 2Instituto de Pesquisa do Câncer (IPEC), Guarapuava, PR, Brazil. 3Universidade Federal do Paraná (UFPR), Departamento de Neurologia, Hospital de Clínicas, Curitiba, PR, Brazil. 4 Instituto de Neurologia de Curitiba (INC), Ambulatório de Distúrbios da Memória e Comportamento, Demência e Outros Transtornos Cognitivos e Comportamentais, Curitiba, PR, Brazil. 5Karolinska Institutet, Care Sciences and Society, Department of Neurobiology, Stockholm, Sweden. Abstract The choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) are fundamental to neurophysiological functions of the central cholinergic system. We confirmed and quantified the presence of extracellular ChAT protein in human plasma and also characterized ChAT and VAChT polymorphisms, protein and activity levels in plasma of Alzheimer’s disease patients (AD; N = 112) and in cognitively healthy controls (EC; N = 118). We found no significant differences in plasma levels of ChAT activity and protein between AD and EC groups. Although no differences were observed in plasma ChAT activity and protein concentration among ChEI-treated and untreated AD patients, ChAT activity and protein levels variance in plasma were higher among the rivastigmine- treated group (ChAT protein: p = 0.005; ChAT activity: p = 0.0002).
    [Show full text]
  • Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed Hipscs To
    Hindawi Publishing Corporation Stem Cells International Volume 2013, Article ID 784629, 25 pages http://dx.doi.org/10.1155/2013/784629 Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny Leonhard Linta,1 Marianne Stockmann,1 Qiong Lin,2 André Lechel,3 Christian Proepper,1 Tobias M. Boeckers,1 Alexander Kleger,3 and Stefan Liebau1 1 InstituteforAnatomyCellBiology,UlmUniversity,Albert-EinsteinAllee11,89081Ulm,Germany 2 Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany 3 Department of Internal Medicine I, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany Correspondence should be addressed to Alexander Kleger; [email protected] and Stefan Liebau; [email protected] Received 31 January 2013; Accepted 6 March 2013 Academic Editor: Michael Levin Copyright © 2013 Leonhard Linta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated.
    [Show full text]
  • Acetylcholine Revisited Were Effective Does Suggest That the Observed Effect Was Due to Ach Release Anders Bjorklund and Stephen B
    NEWS AND VIEWS COGNITIVE FUNCTION------------------------------ bearing the choline acetyltransferase gene Acetylcholine revisited were effective does suggest that the observed effect was due to ACh release Anders Bjorklund and Stephen B. Dunnett and activation of cholinergic receptors in the area surrounding the transplants. This IF impaired cortical cholinergic function afferent neuronal connections. is compatible with studies in which deficits associated with damage to the basal fore­ This brings us to what the new studl associated with forebrain cholinergic brain cholinergic neuron system is in­ can tell us about the normal role of the damage are alleviated by cholinomimetic strumental in dementia-related cognitive forebrain cholinergic system in cognitive drugs such as physostigmine or tacrine. declinel,2, then restoration of forebrain function. Interpretation of the data of Moreover, non-cholinergic drugs that act cholinergic neurotransmission might be Winkler et al. is by no means straightfor­ to enhance cortical function in a more enough to improve at least some aspects of ward in this respect. There is the question general way can provide a similar recovery impaired learning and memory, particu­ of specificity at three levels- whether the of the behavioural deficits associated with larly in conditions such as Alzheimer's functional deficit induced by excitotoxic NBM lesions and other types of cho­ 11 12 disease. The neurotransmitter acetylcho­ NBM lesions (and, by inference, in linergic blockade • . This suggests that a line (ACh) is suspected to be an important Alzheimer's dementia) is indeed cho­ pharmacological reversal of deficits acting participant in the maintenance of normal linergic, cortical and cognitive in nature, at the neocortical level can be mediated cognitive function, but it is not clear to which may not be the case.
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • Nicotinic Receptor Gene Variants Interact with Attention Deficient
    Addictive Behaviors 38 (2013) 2683–2689 Contents lists available at ScienceDirect Addictive Behaviors Nicotinic receptor gene variants interact with attention deficient hyperactive disorder symptoms to predict smoking trajectories from early adolescence to adulthood Chien-Ti Lee a, Bernard F. Fuemmeler a,b,⁎, F. Joseph McClernon c,d, Allison Ashley-Koch e, Scott H. Kollins c a Duke University Medical Center, Department of Psychology Neuroscience, Durham, NC DUMC 104006, Durham, NC 27710, United States b Duke University, Department of Community and Family Medicine, Durham, NC DUMC 104006, Durham, NC 27710, United States c Duke University Medical Center, Department of Psychiatry and Behavioral Science, Durham, NC DUMC 3527, Durham, NC 27710, United States d Durham VAMC Mental Illness Research, Education, and Clinical Center, Durham, NC 508 Fulton Street, Durham, NC 27705, United States e Duke University Medical Center, Center for Human Genomics, DUMC Box 2903, Durham, NC 27710, United States HIGHLIGHTS • Associations between nAChR SNPs, ADHD symptoms, and smoking patterns were examined. • Growth modeling used to identify smoking patterns based on SNP and ADHD symptoms. • ADHD symptom severity predicted the number of cigarettes smoked. • Certain CHRNA6 variants predicted pattern of cigarette use over time. • CHRNB3 variant × ADHD symptom interaction increased risk of cigarette use over time. article info abstract Keywords: Objective: To examine the association of single nucleotide polymorphisms (SNPs) of the CHRNB3 nAChR SNPs (rs13280604) and CHRNA6 (rs892413) nicotinic acetylcholine receptor (nAChR) genes and symptoms of ADHD attention deficit hyperactivity disorder (ADHD) in predicting smoking patterns from early adolescence to Smoking development adulthood. Method: A longitudinal cohort of 1137 unrelated youths from the National Longitudinal Study of Adolescent Health provided responses to four surveys from Waves I to IV, and a genetic sample in Wave III.
    [Show full text]
  • Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence
    G C A T T A C G G C A T genes Article Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence Lingjun Zuo 1, Rolando Garcia-Milian 2, Xiaoyun Guo 1,3,4,*, Chunlong Zhong 5,*, Yunlong Tan 6, Zhiren Wang 6, Jijun Wang 3, Xiaoping Wang 7, Longli Kang 8, Lu Lu 9,10, Xiangning Chen 11,12, Chiang-Shan R. Li 1 and Xingguang Luo 1,6,* 1 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; [email protected] (L.Z.); [email protected] (C.-S.R.L.) 2 Curriculum & Research Support Department, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, CT 06510, USA; [email protected] 3 Shanghai Mental Health Center, Shanghai 200030, China; [email protected] 4 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA 5 Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China 6 Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing 100096, China; [email protected] (Y.T.); [email protected] (Z.W.) 7 Department of Neurology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai 200080, China; [email protected] 8 Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Diseases of Tibet Autonomous Region, Xizang Minzu University School of Medicine, Xianyang, Shanxi 712082, China; [email protected] 9 Provincial Key Laboratory for Inflammation and Molecular Drug Target, Medical
    [Show full text]
  • Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology
    brain sciences Review Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology Andrea Becchetti 1,* , Laura Clara Grandi 1 , Giulia Colombo 1 , Simone Meneghini 1 and Alida Amadeo 2 1 Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milano, Italy; [email protected] (L.C.G.); [email protected] (G.C.); [email protected] (S.M.) 2 Department of Biosciences, University of Milano, 20133 Milano, Italy; [email protected] * Correspondence: [email protected] Received: 13 October 2020; Accepted: 21 November 2020; Published: 25 November 2020 Abstract: Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic focal seizures, mainly arising in the neocortex during non-rapid eye movements (NREM) sleep. The familial form is autosomal dominant SHE (ADSHE), which can be caused by mutations in genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR), Na+-gated K+ channels, as well as non-channel signaling proteins, such as components of the gap activity toward rags 1 (GATOR1) macromolecular complex. The causative genes may have different roles in developing and mature brains. Under this respect, nicotinic receptors are paradigmatic, as different pathophysiological roles are exerted by distinct nAChR subunits in adult and developing brains. The widest evidence concerns α4 and β2 subunits. These participate in heteromeric nAChRs that are major modulators of excitability in mature neocortical circuits as well as regulate postnatal synaptogenesis. However, growing evidence implicates mutant α2 subunits in ADSHE, which poses interpretive difficulties as very little is known about the function of α2-containing (α2*) nAChRs in the human brain.
    [Show full text]
  • Nicotinic Acetylcholine Receptor Variation and Response to Smoking Cessation Therapies Andrew W
    94 Original article Nicotinic acetylcholine receptor variation and response to smoking cessation therapies Andrew W. Bergena, Harold S. Javitza, Ruth Krasnowa, Denise Nishitaa, Martha Michela, David V. Contib, Jinghua Liub, Won Leeb, Christopher K. Edlundb, Sharon Hallc, Pui-Yan Kwokd, Neal L. Benowitze, Timothy B. Bakerf, Rachel F. Tyndaleh, Caryn Lermang and Gary E. Swana Objective To evaluate the association of nicotinic and with increased abstinence in the NRT PG at 6MO acetylcholine receptor (nAChR) single nucleotide [for rs588765, 2.07 (1.11–3.87) and for rs1051730, 2.54 polymorphism (SNP) with 7-day point prevalence (1.29–4.99)]. We observed significant heterogeneity abstinence (abstinence) in randomized clinical trials in rs1051730 effects (F = 2.48, P = 0.021) between PGs. of smoking cessation therapies in individuals grouped Conclusion chr15q25.1 nAChR SNP risk alleles for by pharmacotherapy randomization to inform the smoking heaviness significantly increase relapse with PLA development of personalized smoking cessation therapy. treatment and significantly increase abstinence with NRT. Materials and methods We quantified association of four These SNP–PG associations require replication SNPs at three nAChRs with abstinence in eight randomized in independent samples for validation, and testing in larger clinical trials. Participants were 2633 outpatient treatment- sample sizes to evaluate whether similar effects occur in seeking, self-identified European ancestry individuals other PGs. Pharmacogenetics and Genomics 23:94–103 c
    [Show full text]
  • The Functional Role of a Human Polymorphism (Rs2304297) in the 3'-UTR of the CHRNA6 Gene in Nicotine-Induced Locomotion and An
    Submitter Name: Anjelica Cardenas Submitted email: [email protected] PI Name (if different): Shahrdad Lotfipour, PhD PI email (if different): [email protected] The Functional Role of a Human Polymorphism (rs2304297) in the 3’-UTR of the CHRNA6 Gene in Nicotine-Induced Locomotion and Anxiety in Adolescent Sprague Dawley Rats Anjelica Cardenas1, Yasamin Heydary1, Shahrdad Lotfipour1,2,3 1Pharmaceutical Sciences, University of California, Irvine; 2Emergency Medicine, University of California, Irvine, 3Pathology and Laboratory Medicine, University of California, Irvine A single nucleotide polymorphism (SNP), rs2304297, in the human 3’-untranslated region (UTR) of the alpha(α)6 nicotinic acetylcholine receptor (nAChR) subunit gene (CHRNA6), is associated with enhanced smoking during adolescence in humans. The α6 nAChR subunit exhibits peak expression during adolescence in dopaminergic neurons of the ventral tegmental area and substantia nigra in rodents. Studies using α6 genetic animal models and pharmacological approaches provide evidence that α6-containing (*) nAChRs mediate nicotine-induced locomotor activity, anxiety, and self-administration. To study the role of the human CHRNA6 3’-UTR SNP in vivo, our lab generated a humanized rodent line via CRISPR/Cas9 genomic engineering. Using our new genetic animal model, our current studies test the functional role of the SNP in adolescent locomotor response and anxiety-like behavior following acute and sub-chronic nicotine exposure. We hypothesize that the CHRNA6 SNP will interact with nicotine to enhance locomotion and anxiolytic behavior in male and female humanized 3’-UTR CHRNA6 rats. Our results illustrate sub-chronic, but not acute, nicotine exposure leads to genotype- and sex-dependent enhancement of locomotion. For anxiety-like behavior, we observe genotype-dependent effects for acute nicotine exposure and genotype- and sex-dependent effects for sub-chronic nicotine versus saline exposure.
    [Show full text]
  • The Relationship Between Cholinergic and Noradrenergic Activity and Behavioral State
    THE RELATIONSHIP BETWEEN CHOLINERGIC AND NORADRENERGIC ACTIVITY AND BEHAVIORAL STATE by JOHN JOSEPH FRANCIS A THESIS Presented to the Department of Biology and the Robert D. Clark Honors College in partial fulfillment of the requirements for the degree of Bachelor of Science May 2021 An Abstract of the Thesis of John Joseph Francis for the degree of Bachelor of Science in the Department of Biology to be taken June 2021 Title: The Relationship Between Cholinergic and Noradrenergic Activity and Behavioral State Approved: ______David McCormick, Ph.D.____ Primary Thesis Advisor Approved: ______Lindsay Collins, Ph.D.________ Second Reader Approved: ___ Adam Miller, Ph.D._ ______ Biology Honors Faculty Representative Approved: _______Chris Sinclair, Ph.D._______ Clark Honors College Representative Animal behaviors result from complex network activity in the brain. Precise excitation and inhibition within these networks are partially regulated by neuromodulatory systems that regulate the behavior of other neurons, influencing brain processing and ultimately the animal’s behavior. This regulation is accomplished, in part, by the neuromodulators acetylcholine (ACh) and noradrenaline (NA). ACh and NA are produced and released by cholinergic and noradrenergic neurons, respectively, and have broad functions throughout the central nervous system. This project investigates the relationship between ACh and NA neuromodulatory activity and ii behavioral state with respect to arousal and behavior-dependent modes of neuromodulation. Using systems neuroscience techniques, such as intracranial viral injections and two-photon microscopy, this project offers novel insights into the dynamic relationship between ACh and NA activity and behavioral state in mice. First, I confirm previous findings of a strong relationship between neuromodulatory activity and arousal state, as measured by walking velocity, whisking, and pupil dilation/constriction.
    [Show full text]
  • Resequencing of Nicotinic Acetylcholine Receptor Genes and Association of Common and Rare Variants with the Fagerstro¨M Test for Nicotine Dependence
    Neuropsychopharmacology (2010) 35, 2392–2402 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 $32.00 www.neuropsychopharmacology.org Resequencing of Nicotinic Acetylcholine Receptor Genes and Association of Common and Rare Variants with the Fagerstro¨m Test for Nicotine Dependence 1,4 1 2 2 1 Jennifer Wessel , Sarah M McDonald , David A Hinds , Renee P Stokowski , Harold S Javitz , 2 1 2 1 2 1 Michael Kennemer , Ruth Krasnow , William Dirks , Jill Hardin , Steven J Pitts , Martha Michel , 1 2 3 1 ,1 Lisa Jack , Dennis G Ballinger , Jennifer B McClure , Gary E Swan and Andrew W Bergen* 1 2 3 Center for Health Sciences, SRI International, Menlo Park, CA, USA; Perlegen Sciences, Mountain View, CA, USA; Group Health Research 4 Institute, Seattle, WA, USA; Department of Public Health, Indiana University School of Medicine, Indianapolis, IN, USA Common single-nucleotide polymorphisms (SNPs) at nicotinic acetylcholine receptor (nAChR) subunit genes have previously been associated with measures of nicotine dependence. We investigated the contribution of common SNPs and rare single-nucleotide variants (SNVs) in nAChR genes to Fagerstro¨m test for nicotine dependence (FTND) scores in treatment-seeking smokers. Exons of 10 genes were resequenced with next-generation sequencing technology in 448 European-American participants of a smoking cessation trial, and CHRNB2 and CHRNA4 were resequenced by Sanger technology to improve sequence coverage. A total of 214 SNP/SNVs were identified, of which 19.2% were excluded from analyses because of reduced completion rate, 73.9% had minor allele frequencies o5%, and 48.1% were novel relative to dbSNP build 129.
    [Show full text]