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?4-GABAA receptors of hippocampal pyramidal neurons are associated with resilience against activity-based anorexia for adolescent female mice but not for males.

ABSTRACT: Activity-based anorexia (ABA) is an animal model of anorexia nervosa, a mental illness with highest mortality and with onset that is most frequently during adolescence. We questioned whether vulnerability of adolescent mice to ABA differs between sexes and whether individual differences in resilience are causally linked to ?4??-GABAAR expression. C57BL6/J WT and ?4-KO adolescent male and female mice underwent ABA induction by combining wheel access with food restriction. ABA vulnerability was measured as the extent of food restriction-evoked hyperactivity on a running wheel and body weight losses. ?4??-GABAAR levels at plasma membranes of pyramidal cells in dorsal hippocampus were assessed by electron microscopic immunocytochemistry. Temporal patterns and extent of weight loss during ABA induction were similar between sexes. Both sexes also exhibited individual differences in ABA vulnerability. Correlation analyses revealed that, for both sexes, body weight changes precede and thus are likely to drive suppression of wheel running. However, the suppression was during the food-anticipatory hours for males, while for females, suppression was delayed by a day and during food-access hours. Correspondingly, only females adaptively increased food intake. ABA induced up-regulation of ?4??-GABAARs at plasma membranes of dorsal hippocampal pyramidal cells of females, and especially those females exhibiting resilience. Conversely, ?4-KO females exhibited greater food restriction-evoked hyperactivity than WT females. In contrast, ABA males did not up-regulate ?4??-GABAARs, did not exhibit genotype differences in vulnerability, and exhibited no correlation between plasmalemmal ?4??-GABAARs and ABA resilience. Thus, food restriction-evoked hyperactivity is driven by anxiety but can be suppressed through upregulation of hippocampal ?4??-GABAARs for females but not for males. This knowledge of sex-related differences in the underlying mechanisms of resilience to ABA indicates that drugs targeting ?4??-GABAARs may be helpful for treating stress-induced anxiety and anorexia nervosa of females but not males.

SUBMITTER: Chen YW

PROVIDER: S-EPMC6197931 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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α4-GABA<sub>A</sub> receptors of hippocampal pyramidal neurons are associated with resilience against activity-based anorexia for adolescent female mice but not for males.

Chen Yi-Wen YW Actor-Engel Hannah H Aoki Chiye C

Molecular and cellular neurosciences 20180422

Activity-based anorexia (ABA) is an animal model of anorexia nervosa, a mental illness with highest mortality and with onset that is most frequently during adolescence. We questioned whether vulnerability of adolescent mice to ABA differs between sexes and whether individual differences in resilience are causally linked to α4βδ-GABA<sub>A</sub>R expression. C57BL6/J WT and α4-KO adolescent male and female mice underwent ABA induction by combining wheel access with food restriction. ABA vulnerabi ...[more]

PMID: 29684457

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Project description:In the hippocampus, signaling through G protein-coupled receptors is modulated by Regulators of G protein signaling (Rgs) proteins, which act to stimulate the rate of GTP hydrolysis, and consequently, G protein inactivation. The R7-Rgs subfamily selectively deactivates the G(i/o)-class of Gα subunits that mediate the action of several GPCRs. Here, we used co-immunoprecipitation, electrophysiology and immunoelectron microscopy techniques to investigate the formation of macromolecular complexes and spatial relationship of Rgs7/Gβ5 complexes and its prototypical signaling partners, the GABAB receptor and Girk channel. Co-expression of recombinant GABAB receptors and Girk channels in combination with co-immunoprecipitation experiments established that the Rgs7/Gβ5 forms complexes with GABAB receptors or Girk channels. Using electrophysiological experiments, we found that GABAB -Girk current deactivation kinetics was markedly faster in cells coexpressing Rgs7/Gβ5. At the electron microscopic level, immunolabeling for Rgs7 and Gβ5 proteins was found primarily in the dendritic layers of the hippocampus and showed similar distribution patterns. Immunoreactivity was mostly localized along the extrasynaptic plasma membrane of dendritic shafts and spines of pyramidal cells and, to a lesser extent, to that of presynaptic terminals. Quantitative analysis of immunogold particles for Rgs7 and Gβ5 revealed an enrichment of the two proteins around excitatory synapses on dendritic spines, virtually identical to that of Girk2 and GABAB1 . These data support the existence of macromolecular complexes composed of GABAB receptor-G protein-Rgs7-Girk channels in which Rgs7 and Gβ5 proteins may preferentialy modulate GABAB receptor signaling through the deactivation of Girk channels on dendritic spines. In contrast, Rgs7 and Girk2 were associated but mainly segregated from GABAB1 in dendritic shafts, where Rgs7/Gβ5 signaling complexes might modulate Girk-dependent signaling via a different metabotropic receptor(s).

Dataset Information

?4-GABAA receptors of hippocampal pyramidal neurons are associated with resilience against activity-based anorexia for adolescent female mice but not for males.

Publications

α4-GABA<sub>A</sub> receptors of hippocampal pyramidal neurons are associated with resilience against activity-based anorexia for adolescent female mice but not for males.

Similar Datasets

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