Knockout of the γ-aminobutyric acid receptor subunit α4 reduces functional δ-containing extrasynaptic receptors in hippocampal pyramidal cells at the onset of puberty

Nicole Sabaliauskas, Hui Shen, Gregg E. Homanics, Sheryl S. Smith, Chiye Aoki

Research output: Contribution to journalArticle

Abstract

Increased plasmalemmal localization of α4βδ GABA A receptors (GABARs) occurs in the hippocampal pyramidal cells of female mice at pubertal onset (Shen et al.; 2010). This increase occurs on both dendritic spines and shafts of CA1 pyramidal cells and is in response to hormone fluctuations that occur at pubertal onset. However, little is known about how the α4 and δ subunits individually mediate the formation of functional, plasmalemmal α4βδ GABARs. To determine whether expression of the α4 subunit is necessary for plasmalemmal δ subunit localization at pubertal onset, electron microscopic-immunocytochemistry (EM-ICC) was employed. CA1 pyramidal cells of female α4 knockout (KO) mice were tested for plasmalemmal levels of the δ subunit within dendritic spine and shaft profiles at the onset of puberty. EM-ICC revealed that the α4 and δ subunits localize on dendritic spines and shafts at sites extrasynaptic to GABAergic input at pubertal onset in tissue of wild-type (WT) mice. At pubertal onset, plasmalemmal localization of the δ subunit is reduced 45.9% on dendritic spines, and 56.7% on dendritic shafts with KO of the α4 subunit, as compared to WT tissue, yet levels of intracellular δ immunoreactivity remain unchanged. The decline in plasmalemmal localization is manifested as decreased responsiveness to the GABA agonist gaboxadol at concentrations that are selective for δ-containing GABARs. Additionally, α4 KO mice have larger dendritic spine and shaft profiles. Our findings demonstrate that α4 subunit expression strongly influences the pubertal increase of δ subunits at the plasma membrane, and that genetic deletion of α4 serves as a functional knock-down of δ-containing GABARs.

Original languageEnglish (US)
Pages (from-to)11-23
Number of pages13
JournalBrain Research
Volume1450
DOIs
StatePublished - Apr 23 2012

Fingerprint

Aminobutyrates
Dendritic Spines
Pyramidal Cells
Puberty
GABA-A Receptors
Knockout Mice
Immunohistochemistry
Electrons
GABA Agonists
Cell Membrane
Hormones

Keywords

  • Allopregnanolone
  • Alpha 4
  • Delta
  • GABA type A receptor
  • Puberty
  • THP
  • Tonic inhibition

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Knockout of the γ-aminobutyric acid receptor subunit α4 reduces functional δ-containing extrasynaptic receptors in hippocampal pyramidal cells at the onset of puberty. / Sabaliauskas, Nicole; Shen, Hui; Homanics, Gregg E.; Smith, Sheryl S.; Aoki, Chiye.

In: Brain Research, Vol. 1450, 23.04.2012, p. 11-23.

Research output: Contribution to journalArticle

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abstract = "Increased plasmalemmal localization of α4βδ GABA A receptors (GABARs) occurs in the hippocampal pyramidal cells of female mice at pubertal onset (Shen et al.; 2010). This increase occurs on both dendritic spines and shafts of CA1 pyramidal cells and is in response to hormone fluctuations that occur at pubertal onset. However, little is known about how the α4 and δ subunits individually mediate the formation of functional, plasmalemmal α4βδ GABARs. To determine whether expression of the α4 subunit is necessary for plasmalemmal δ subunit localization at pubertal onset, electron microscopic-immunocytochemistry (EM-ICC) was employed. CA1 pyramidal cells of female α4 knockout (KO) mice were tested for plasmalemmal levels of the δ subunit within dendritic spine and shaft profiles at the onset of puberty. EM-ICC revealed that the α4 and δ subunits localize on dendritic spines and shafts at sites extrasynaptic to GABAergic input at pubertal onset in tissue of wild-type (WT) mice. At pubertal onset, plasmalemmal localization of the δ subunit is reduced 45.9{\%} on dendritic spines, and 56.7{\%} on dendritic shafts with KO of the α4 subunit, as compared to WT tissue, yet levels of intracellular δ immunoreactivity remain unchanged. The decline in plasmalemmal localization is manifested as decreased responsiveness to the GABA agonist gaboxadol at concentrations that are selective for δ-containing GABARs. Additionally, α4 KO mice have larger dendritic spine and shaft profiles. Our findings demonstrate that α4 subunit expression strongly influences the pubertal increase of δ subunits at the plasma membrane, and that genetic deletion of α4 serves as a functional knock-down of δ-containing GABARs.",
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AU - Shen, Hui

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