Dataset Information

Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors.

ABSTRACT: Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the ?7 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 ?7 nAChRs and is recapitulated by GTS-21, an ?7 nAChR partial agonist. Pharmacotherapies potentiating ?7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the ?7 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 ?7 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 ?7 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 ?7 nAChRs in regulation of aggression, and demonstrate that hippocampal ?7 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.

SUBMITTER: Lewis AS

PROVIDER: S-EPMC5916354 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors.

Lewis Alan S AS Pittenger Steven T ST Mineur Yann S YS Stout Dawson D Smith Philip H PH Picciotto Marina R MR

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20171107 6

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 t ...[more]

PMID: 29114104

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Project description:Nicotinic acetylcholine receptors (nAChRs) are known to play a role in cognitive functions of the hippocampus, such as memory consolidation. Given that they conduct Ca2+ and are capable of regulating the release of glutamate and γ-aminobutyric acid (GABA) within the hippocampus, thereby shifting the excitatory-inhibitory ratio, we hypothesized that the activation of nAChRs will result in the potentiation of hippocampal networks and alter synchronization. We used nicotine as a tool to investigate the impact of activation of nAChRs on neuronal network dynamics in primary embryonic rat hippocampal cultures prepared from timed-pregnant Sprague-Dawley rats. We perturbed cultured hippocampal networks with increasing concentrations of bath-applied nicotine and performed network extracellular recordings of action potentials using a microelectrode array. We found that nicotine modulated network dynamics in a concentration-dependent manner; it enhanced firing of action potentials as well as facilitated bursting activity. In addition, we used pharmacological agents to determine the contributions of discrete nAChR subtypes to the observed network dynamics. We found that β4-containing nAChRs are necessary for the observed increases in spiking, bursting, and synchrony, while the activation of α7 nAChRs augments nicotine-mediated network potentiation but is not necessary for its manifestation. We also observed that antagonists of N-methyl-D-aspartate receptors (NMDARs) and group I metabotropic glutamate receptors (mGluRs) partially blocked the effects of nicotine. Furthermore, nicotine exposure promoted autophosphorylation of Ca2+ /calmodulin-dependent kinase II (CaMKII) and serine 831 phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit GluA1. These results suggest that nicotinic receptors induce potentiation and synchronization of hippocampal networks and glutamatergic synaptic transmission. Findings from this work highlight the impact of cholinergic signaling in generating network-wide potentiation in the form of enhanced spiking and bursting dynamics that coincide with molecular correlates of memory such as increased phosphorylation of CaMKII and GluA1. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Dataset Information

Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors.

Publications

Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors.

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