gamma-Aminobutyric acid(A) receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development.
Profound alterations in the function of GABA occur over the course of postnatal development. Changes in GABA(A) 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 GABA(A) 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 GABA(A) receptor subunit mRNA expression, including greater than two-fold lower expression of alpha1-, alpha4- and gamma2-subunit mRNAs and 10-fold higher expression of alpha5-mRNA in immature compared with adult neurons. These differences correlate both with regional changes in subunit protein level and with alterations in GABA(A) 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 GABA(A) 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 GABA(A) receptor function during postnatal development.
Brooks-Kayal
A R
AR
Pediatric Regional Epilepsy Program and Joseph Stokes Research Institute of The Children's Hospital of Philadelphia, PA 19104, USA. kayal@email.chop.edu
Shumate
M D
MD
Jin
H
H
Rikhter
T Y
TY
Kelly
M E
ME
Coulter
D A
DA
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D004396:Coloring Agents; D018891:Dentate Gyrus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D015032:Zinc / Q000494:pharmacology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D004396:Coloring Agents; D006993:Hypnotics and Sedatives; D011725:Pyridines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; D015032:Zinc