Hippocampal changes produced by overexpression of the human CHRNA5/A3/B4 gene cluster may underlie cognitive deficits rescued by nicotine in transgenic mice.
Addiction involves long-lasting maladaptive changes including development of disruptive drug-stimuli associations. Nicotine-induced neuroplasticity underlies the development of tobacco addiction but also, in regions such as the hippocampus, the ability of this drug to enhance cognitive capabilities. Here, we propose that the genetic locus of susceptibility to nicotine addiction, the CHRNA5/A3/B4 gene cluster, encoding the α5, α3 and β4 subunits of the nicotinic acetylcholine receptors (nAChRs), may influence nicotine-induced neuroadaptations. We have used transgenic mice overexpressing the human cluster (TgCHRNA5/A3/B4) to investigate hippocampal structure and function in genetically susceptible individuals. TgCHRNA5/A3/B4 mice presented a marked reduction in the dendrite complexity of CA1 hippocampal pyramidal neurons along with an increased dendritic spine density. In addition, TgCHRNA5/A3/B4 exhibited increased VGLUT1/VGAT ratio in the CA1 region, suggesting an excitatory/inhibitory imbalance. These hippocampal alterations were accompanied by a significant impairment in short-term novelty recognition memory. Interestingly, chronic infusion of nicotine (3.25 mg/kg/d for 7 d) was able to rescue the reduced dendritic complexity, the excitatory/inhibitory imbalance and the cognitive impairment in TgCHRNA5/A3/B4. Our results suggest that chronic nicotine treatment may represent a compensatory strategy in individuals with altered expression of the CHRNA5/A3/B4 region.
Cellular and Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation (CRG), Barcelona Biomedical Research Park (PRBB) building, Room 522.04; C/ Dr. Aiguader 88, E-08003, Barcelona, Spain. Susanna.Casacuberta@umassmed.edu.|Universitat Pompeu Fabra (UPF), E-08003, Barcelona, Spain. Susanna.Casacuberta@umassmed.edu.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), E-08003, Barcelona, Spain. Susanna.Casacuberta@umassmed.edu.
Susanna
S
Molas
Cellular and Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation (CRG), Barcelona Biomedical Research Park (PRBB) building, Room 522.04; C/ Dr. Aiguader 88, E-08003, Barcelona, Spain. thomas.gener@crg.eu.|Universitat Pompeu Fabra (UPF), E-08003, Barcelona, Spain. thomas.gener@crg.eu.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), E-08003, Barcelona, Spain. thomas.gener@crg.eu.
Thomas
T
Gener
Cellular and Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation (CRG), Barcelona Biomedical Research Park (PRBB) building, Room 522.04; C/ Dr. Aiguader 88, E-08003, Barcelona, Spain. jofre_guellb@hotmail.com.
Jofre
J
Güell
Department of Inorganic, Organic Chemistry and Biochemistry, Faculty of Medicine, Centro Regional de Investigaciones Biomédicas (CRIB), University of Castilla la Mancha, E-13071, Ciudad Real, Spain. mairena.martin@uclm.es.|Department of Inorganic, Organic Chemistry and Biochemistry, Faculty of Chemical Sciences and Techonologies, CRIB, University of Castilla la Mancha, E-13071, Ciudad Real, Spain. mairena.martin@uclm.es.
Mairena
M
Martín
Department of Inorganic, Organic Chemistry and Biochemistry, Faculty of Medicine, Centro Regional de Investigaciones Biomédicas (CRIB), University of Castilla la Mancha, E-13071, Ciudad Real, Spain. Inmaculada.BYanez@uclm.es.
Inmaculada
I
Ballesteros-Yáñez
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), E-08036, Barcelona, Spain. msanche3@clinic.ub.es.|Institució Catalana de Recerca i Estudis Avançats (ICREA), E-08010, Barcelona, Spain. msanche3@clinic.ub.es.
Maria V
MV
Sanchez-Vives
Cellular and Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation (CRG), Barcelona Biomedical Research Park (PRBB) building, Room 522.04; C/ Dr. Aiguader 88, E-08003, Barcelona, Spain. mara.dierssen@crg.es.|Universitat Pompeu Fabra (UPF), E-08003, Barcelona, Spain. mara.dierssen@crg.es.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), E-08003, Barcelona, Spain. mara.dierssen@crg.es.
Mara
M
Dierssen
D000818:Animals; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
D009419:Nerve Tissue Proteins; D009538:Nicotine; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D011978:Receptors, Nicotinic; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human; C493465:Slc17a7 protein, mouse; C492244:Viaat protein, mouse