γ-Aminobutyric acidA receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development

Authors

  • Amy R. Brooks-Kayal,

    1. Pediatric Regional Epilepsy Program and Joseph Stokes Research Institute of The Children's Hospital of Philadelphia, Philadelphia, USA
      Departments of
    2. Pediatrics and
    3. Neurology, University of Pennsylvania, Pennsylvania, USA
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  • Melissa D. Shumate,

    1. Department of Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
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  • Hong Jin,

    1. Pediatric Regional Epilepsy Program and Joseph Stokes Research Institute of The Children's Hospital of Philadelphia, Philadelphia, USA
      Departments of
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  • Tatiana Y. Rikhter,

    1. Pediatric Regional Epilepsy Program and Joseph Stokes Research Institute of The Children's Hospital of Philadelphia, Philadelphia, USA
      Departments of
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  • Mary Ellen Kelly,

    1. Pediatric Regional Epilepsy Program and Joseph Stokes Research Institute of The Children's Hospital of Philadelphia, Philadelphia, USA
      Departments of
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  • Douglas A. Coulter

    1. Pediatric Regional Epilepsy Program and Joseph Stokes Research Institute of The Children's Hospital of Philadelphia, Philadelphia, USA
      Departments of
    2. Pediatrics and
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Address correspondence and reprint requests to Dr Amy Brooks-Kayal, Division of Neurology, Children's Hospital of Philadelphia, Abramson Pediatric Research Center, Rm 502, 3516 Civic Center Blvd., Philadelphia, PA 19104, USA. E-mail: kayal@email.chop.edu

Abstract

Profound alterations in the function of GABA occur over the course of postnatal development. Changes in GABAA receptor expression are thought to contribute to these differences in GABAergic function, but how subunit changes correlate with receptor function in individual developing neurons has not been defined precisely. In the current study, we correlate expression of 14 different GABAA receptor subunit mRNAs with changes in the pharmacological properties of the receptor in individual hippocampal dentate granule cells over the course of postnatal development in rat. We demonstrate significant developmental differences in GABAA receptor subunit mRNA expression, including greater than two-fold lower expression of α1-, α4- and γ2-subunit mRNAs and 10-fold higher expression of α5-mRNA in immature compared with adult neurons. These differences correlate both with regional changes in subunit protein level and with alterations in GABAA receptor function in immature dentate granule cells, including two-fold higher blockade by zinc and three-fold lower augmentation by type-I benzodiazepine site modulators. Further, we find an inverse correlation between changes in GABAA receptor zinc sensitivity and abundance of vesicular zinc in dentate gyrus during postnatal development. These findings suggest that developmental differences in subunit expression contribute to alterations in GABAA receptor function during postnatal development.

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