| First Author | Lewis AS | Year | 2018 |
| Journal | Neuropsychopharmacology | Volume | 43 |
| Issue | 6 | Pages | 1267-1275 |
| PubMed ID | 29114104 | Mgi Jnum | J:318516 |
| Mgi Id | MGI:6859946 | Doi | 10.1038/npp.2017.276 |
| Citation | Lewis AS, et al. (2018) Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors. Neuropsychopharmacology 43(6):1267-1275 |
| abstractText | Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the alpha7 nicotinic acetylcholine receptor (nAChR), and manifest a variable neuropsychiatric phenotype that frequently includes persistent aggression. In mice, nAChR activation by nicotine is anti-aggressive, or 'serenic,' an effect which requires alpha7 nAChRs and is recapitulated by GTS-21, an alpha7 nAChR partial agonist. Pharmacotherapies potentiating alpha7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the alpha7 nAChR as an important regulator of aggressive behavior, but the underlying neurobiological substrates remain to be determined. We therefore investigated the brain regions and potential neural circuits in which alpha7 nAChRs regulate aggressive behavior in male mice. As in 15q13.3DS, mice heterozygous for Chrna7 were significantly more aggressive compared to wild-type controls in the resident-intruder test. We subsequently examined the hippocampus, where alpha7 nAChRs are highly expressed, particularly in GABAergic interneurons. Resident-intruder interactions strongly activated granule cells in the dentate gyrus (DG). In contrast, GTS-21, which reduces aggression in mice, reduced DG granule cell activity during resident-intruder interactions. Short hairpin RNA knockdown of Chrna7 in the DG enhanced baseline aggression and eliminated the serenic effects of both nicotine and GTS-21 on attack latency. These data further implicate alpha7 nAChRs in regulation of aggression, and demonstrate that hippocampal alpha7 nAChR signaling is necessary and sufficient to limit aggression. These findings suggest that nAChR-mediated regulation of hippocampal excitatory-inhibitory balance could be a promising therapeutic intervention for aggression arising in certain forms of neuropsychiatric disease. |
