Hippocampal changes produced by overexpression of the human CHRNA5/A3/B4 gene cluster may underlie cognitive deficits rescued by nicotine in transgenic mice

• Published in: Acta neuropathologica communications Vol. 2; no. 1; p. 147
• Main Authors: Molas, Susanna, Gener, Thomas, Güell, Jofre, Martín, Mairena, Ballesteros-Yáñez, Inmaculada, Sanchez-Vives, Maria V, Dierssen, Mara
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.11.2014; BioMed Central
• Subjects: Animals; Cells, Cultured; Cognició; Cognition; Cognition Disorders - drug therapy; Cognition Disorders - metabolism; Cognition Disorders - pathology; Dendritic Spines - drug effects; Dendritic Spines - metabolism; Dendritic Spines - pathology; Disease susceptibility; Genetic aspects; Hipocamp (Cervell); Hippocampus (Brain); Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Humans; Male; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; Neuroplasticitat; Neuroplasticity; Nicotina; Nicotine; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Nootropic Agents - pharmacology; Pyramidal Cells - drug effects; Pyramidal Cells - metabolism; Pyramidal Cells - pathology; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Recognition (Psychology) - drug effects; Recognition (Psychology) - physiology; Risk factors; Vesicular Glutamate Transport Protein 1 - metabolism; Vesicular Inhibitory Amino Acid Transport Proteins - metabolism
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-014-0147-1

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.