Adolescent female rats exhibiting activity-based anorexia express elevated levels of GABA A receptor α4 and δ subunits at the plasma membrane of hippocampal CA1 spines

Chiye Aoki, Nicole Sabaliauskas, Tara Chowdhury, Jung Yun Min, Anna Rita Colacino, Kevin Laurino, Nicole C. Barbarich-Marsteller

Research output: Contribution to journalArticle

Abstract

Activity-based anorexia (ABA) is an animal model for anorexia nervosa that has revealed genetic links to anxiety traits and neurochemical characteristics within the hypothalamus. However, few studies have used this animal model to investigate the biological basis for vulnerability of pubertal and adolescent females to ABA, even though the great majority of the anorexia nervosa cases are females exhibiting the first symptoms during puberty. GABAergic inhibition of the hippocampus strongly regulates anxiety as well as plasticity throughout life. We recently showed that the hippocampal CA1 of female mice undergo a dramatic change at puberty onset-from expressing virtually none of the nonsynaptic α4βδ GABA A receptors (GABARs) prepubertally to expressing these GABARs at ∼7% of the CA1 dendritic spine membranes at puberty onset. Furthermore, we showed that this change underlies the enhanced modulation of anxiety, neuronal excitability, and NMDA receptor-dependent synaptic plasticity in the hippocampus by the stress neurosteroid, THP (3α-OH-5α[β]-pregnan-20-one or [allo]pregnanolone). Here, we used quantitative electron microscopy to determine whether ABA induction in female rats during adolescence also elevates the expression of α4 and δ subunits of α4βδ GABARs, as was observed at puberty onset for mice. Our analysis revealed that rats also exhibit a rise of α4 and δ subunits of α4βδ GABARs at puberty onset, in that these subunits are detectable at ∼6% of the dendritic spine membranes of CA1 pyramidal cells at puberty onset (postnatal day 32-36; P32-36) but this drops to about 2% by P40-P44. The levels of α4 and δ subunits at the CA1 spines remained low following exposure of females to either of the two environmental factors needed to generate ABA-food restriction and access to a running wheel for 4 days-from P40 to P44. This pattern contrasted greatly from those of ABA animals, for which the two environmental factors were combined. Within the hippocampus of ABA animals, 12% of the spine profiles were labeled for α4, reflecting a sixfold increase, relative to hippocampi of age-matched (P44) control females (p < 0.005). Concurrently, 7% of the spine profiles were labeled for δ, reflecting a 130% increase from the control values of 3% (p = 0.01). No measurable change was detected for spine size. The observed magnitude of increase in the α4 and δ subunits at spines is sufficient to increase both tonic inhibition of hippocampus and anxiety during stress, thereby likely to exacerbate hyperactivity and weight loss.

Original languageEnglish (US)
Pages (from-to)391-407
Number of pages17
JournalSynapse
Volume66
Issue number5
DOIs
StatePublished - May 2012

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Anorexia
GABA-A Receptors
Puberty
Spine
Cell Membrane
Hippocampus
Anxiety
Dendritic Spines
Anorexia Nervosa
Animal Models
Pregnanolone
Neuronal Plasticity
Membranes
Pyramidal Cells
N-Methyl-D-Aspartate Receptors
Running
Hypothalamus
Neurotransmitter Agents
Weight Loss
Electron Microscopy

Keywords

  • Adolescence
  • Allopregnanolone
  • Anorexia nervosa
  • Anxiety
  • Eating disorder
  • Electron microscopic immunocytochemistry
  • Exercise
  • Food restriction
  • Hippocampus
  • Hyperactivity
  • Mood
  • Pregnanolone
  • Progesterone
  • Puberty
  • Receptor trafficking
  • Stress
  • THP
  • Tonic inhibition

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Adolescent female rats exhibiting activity-based anorexia express elevated levels of GABA A receptor α4 and δ subunits at the plasma membrane of hippocampal CA1 spines. / Aoki, Chiye; Sabaliauskas, Nicole; Chowdhury, Tara; Min, Jung Yun; Colacino, Anna Rita; Laurino, Kevin; Barbarich-Marsteller, Nicole C.

In: Synapse, Vol. 66, No. 5, 05.2012, p. 391-407.

Research output: Contribution to journalArticle

Aoki, Chiye ; Sabaliauskas, Nicole ; Chowdhury, Tara ; Min, Jung Yun ; Colacino, Anna Rita ; Laurino, Kevin ; Barbarich-Marsteller, Nicole C. / Adolescent female rats exhibiting activity-based anorexia express elevated levels of GABA A receptor α4 and δ subunits at the plasma membrane of hippocampal CA1 spines. In: Synapse. 2012 ; Vol. 66, No. 5. pp. 391-407.
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abstract = "Activity-based anorexia (ABA) is an animal model for anorexia nervosa that has revealed genetic links to anxiety traits and neurochemical characteristics within the hypothalamus. However, few studies have used this animal model to investigate the biological basis for vulnerability of pubertal and adolescent females to ABA, even though the great majority of the anorexia nervosa cases are females exhibiting the first symptoms during puberty. GABAergic inhibition of the hippocampus strongly regulates anxiety as well as plasticity throughout life. We recently showed that the hippocampal CA1 of female mice undergo a dramatic change at puberty onset-from expressing virtually none of the nonsynaptic α4βδ GABA A receptors (GABARs) prepubertally to expressing these GABARs at ∼7{\%} of the CA1 dendritic spine membranes at puberty onset. Furthermore, we showed that this change underlies the enhanced modulation of anxiety, neuronal excitability, and NMDA receptor-dependent synaptic plasticity in the hippocampus by the stress neurosteroid, THP (3α-OH-5α[β]-pregnan-20-one or [allo]pregnanolone). Here, we used quantitative electron microscopy to determine whether ABA induction in female rats during adolescence also elevates the expression of α4 and δ subunits of α4βδ GABARs, as was observed at puberty onset for mice. Our analysis revealed that rats also exhibit a rise of α4 and δ subunits of α4βδ GABARs at puberty onset, in that these subunits are detectable at ∼6{\%} of the dendritic spine membranes of CA1 pyramidal cells at puberty onset (postnatal day 32-36; P32-36) but this drops to about 2{\%} by P40-P44. The levels of α4 and δ subunits at the CA1 spines remained low following exposure of females to either of the two environmental factors needed to generate ABA-food restriction and access to a running wheel for 4 days-from P40 to P44. This pattern contrasted greatly from those of ABA animals, for which the two environmental factors were combined. Within the hippocampus of ABA animals, 12{\%} of the spine profiles were labeled for α4, reflecting a sixfold increase, relative to hippocampi of age-matched (P44) control females (p < 0.005). Concurrently, 7{\%} of the spine profiles were labeled for δ, reflecting a 130{\%} increase from the control values of 3{\%} (p = 0.01). No measurable change was detected for spine size. The observed magnitude of increase in the α4 and δ subunits at spines is sufficient to increase both tonic inhibition of hippocampus and anxiety during stress, thereby likely to exacerbate hyperactivity and weight loss.",
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AU - Aoki, Chiye

AU - Sabaliauskas, Nicole

AU - Chowdhury, Tara

AU - Min, Jung Yun

AU - Colacino, Anna Rita

AU - Laurino, Kevin

AU - Barbarich-Marsteller, Nicole C.

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N2 - Activity-based anorexia (ABA) is an animal model for anorexia nervosa that has revealed genetic links to anxiety traits and neurochemical characteristics within the hypothalamus. However, few studies have used this animal model to investigate the biological basis for vulnerability of pubertal and adolescent females to ABA, even though the great majority of the anorexia nervosa cases are females exhibiting the first symptoms during puberty. GABAergic inhibition of the hippocampus strongly regulates anxiety as well as plasticity throughout life. We recently showed that the hippocampal CA1 of female mice undergo a dramatic change at puberty onset-from expressing virtually none of the nonsynaptic α4βδ GABA A receptors (GABARs) prepubertally to expressing these GABARs at ∼7% of the CA1 dendritic spine membranes at puberty onset. Furthermore, we showed that this change underlies the enhanced modulation of anxiety, neuronal excitability, and NMDA receptor-dependent synaptic plasticity in the hippocampus by the stress neurosteroid, THP (3α-OH-5α[β]-pregnan-20-one or [allo]pregnanolone). Here, we used quantitative electron microscopy to determine whether ABA induction in female rats during adolescence also elevates the expression of α4 and δ subunits of α4βδ GABARs, as was observed at puberty onset for mice. Our analysis revealed that rats also exhibit a rise of α4 and δ subunits of α4βδ GABARs at puberty onset, in that these subunits are detectable at ∼6% of the dendritic spine membranes of CA1 pyramidal cells at puberty onset (postnatal day 32-36; P32-36) but this drops to about 2% by P40-P44. The levels of α4 and δ subunits at the CA1 spines remained low following exposure of females to either of the two environmental factors needed to generate ABA-food restriction and access to a running wheel for 4 days-from P40 to P44. This pattern contrasted greatly from those of ABA animals, for which the two environmental factors were combined. Within the hippocampus of ABA animals, 12% of the spine profiles were labeled for α4, reflecting a sixfold increase, relative to hippocampi of age-matched (P44) control females (p < 0.005). Concurrently, 7% of the spine profiles were labeled for δ, reflecting a 130% increase from the control values of 3% (p = 0.01). No measurable change was detected for spine size. The observed magnitude of increase in the α4 and δ subunits at spines is sufficient to increase both tonic inhibition of hippocampus and anxiety during stress, thereby likely to exacerbate hyperactivity and weight loss.

AB - Activity-based anorexia (ABA) is an animal model for anorexia nervosa that has revealed genetic links to anxiety traits and neurochemical characteristics within the hypothalamus. However, few studies have used this animal model to investigate the biological basis for vulnerability of pubertal and adolescent females to ABA, even though the great majority of the anorexia nervosa cases are females exhibiting the first symptoms during puberty. GABAergic inhibition of the hippocampus strongly regulates anxiety as well as plasticity throughout life. We recently showed that the hippocampal CA1 of female mice undergo a dramatic change at puberty onset-from expressing virtually none of the nonsynaptic α4βδ GABA A receptors (GABARs) prepubertally to expressing these GABARs at ∼7% of the CA1 dendritic spine membranes at puberty onset. Furthermore, we showed that this change underlies the enhanced modulation of anxiety, neuronal excitability, and NMDA receptor-dependent synaptic plasticity in the hippocampus by the stress neurosteroid, THP (3α-OH-5α[β]-pregnan-20-one or [allo]pregnanolone). Here, we used quantitative electron microscopy to determine whether ABA induction in female rats during adolescence also elevates the expression of α4 and δ subunits of α4βδ GABARs, as was observed at puberty onset for mice. Our analysis revealed that rats also exhibit a rise of α4 and δ subunits of α4βδ GABARs at puberty onset, in that these subunits are detectable at ∼6% of the dendritic spine membranes of CA1 pyramidal cells at puberty onset (postnatal day 32-36; P32-36) but this drops to about 2% by P40-P44. The levels of α4 and δ subunits at the CA1 spines remained low following exposure of females to either of the two environmental factors needed to generate ABA-food restriction and access to a running wheel for 4 days-from P40 to P44. This pattern contrasted greatly from those of ABA animals, for which the two environmental factors were combined. Within the hippocampus of ABA animals, 12% of the spine profiles were labeled for α4, reflecting a sixfold increase, relative to hippocampi of age-matched (P44) control females (p < 0.005). Concurrently, 7% of the spine profiles were labeled for δ, reflecting a 130% increase from the control values of 3% (p = 0.01). No measurable change was detected for spine size. The observed magnitude of increase in the α4 and δ subunits at spines is sufficient to increase both tonic inhibition of hippocampus and anxiety during stress, thereby likely to exacerbate hyperactivity and weight loss.

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KW - Allopregnanolone

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KW - Anxiety

KW - Eating disorder

KW - Electron microscopic immunocytochemistry

KW - Exercise

KW - Food restriction

KW - Hippocampus

KW - Hyperactivity

KW - Mood

KW - Pregnanolone

KW - Progesterone

KW - Puberty

KW - Receptor trafficking

KW - Stress

KW - THP

KW - Tonic inhibition

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