Journal article
Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors
Neuropsychopharmacology (New York, N.Y.), v 43(6), pp 1267-1275
01 May 2018
PMID: 29114104
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for
CHRNA7
, the gene coding for the α7 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 α7 nAChRs and is recapitulated by GTS-21, an α7 nAChR partial agonist. Pharmacotherapies potentiating α7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the α7 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 α7 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 α7 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 α7 nAChRs in regulation of aggression, and demonstrate that hippocampal α7 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.
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Details
- Title
- Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors
- Creators
- Alan S Lewis - Yale UniversitySteven T Pittenger - Yale UniversityYann S Mineur - Yale UniversityDawson Stout - Yale UniversityPhilip H Smith - CUNY School of LawMarina R Picciotto - Yale University
- Publication Details
- Neuropsychopharmacology (New York, N.Y.), v 43(6), pp 1267-1275
- Publisher
- Nature Publishing Group
- Number of pages
- 9
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000430415100010
- Scopus ID
- 2-s2.0-85045690847
- Other Identifier
- 991022031024804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences
- Pharmacology & Pharmacy
- Psychiatry