Brain-derived Neurotrophic Factor (BDNF)-induced Synthesis of Early Growth Response Factor 3 (Egr3) Controls the Levels of Type A GABA Receptorα4 Subunits in Hippocampal Neurons
Altered function of γ-aminobutyric acid type A receptors (GABAARs) in dentate granule cells of the hippocampus has been associated with temporal lobe epilepsy (TLE) in humans and in animal models of TLE. Such altered receptor function (including increased inhibition by zinc and lack of modulation by...
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Published in | The Journal of biological chemistry Vol. 281; no. 40; pp. 29431 - 29435 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
06.10.2006
American Society for Biochemistry and Molecular Biology |
Online Access | Get full text |
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Summary: | Altered function of γ-aminobutyric acid type A receptors (GABAARs) in dentate granule cells of the hippocampus has been associated with temporal lobe epilepsy (TLE) in humans and in animal models of TLE. Such altered receptor function (including increased inhibition by zinc and lack of modulation by benzodiazepines) is related, in part, to changes in the mRNA levels of certain GABAAR subunits, including α4, and may play a role in epileptogenesis. The majority of GABAARs that contain α4 subunits are extra-synaptic due to lack of the γ2 subunit and presence of δ. However, it has been hypothesized that seizure activity may result in expression of synaptic receptors with altered properties driven by an increased pool of α4 subunits. Results of our previous work suggests that signaling via protein kinase C (PKC) and early growth response factor 3 (Egr3) is the plasticity trigger for aberrant α4 subunit gene (GABRA4) expression after status epilepticus. We now report that brain derived neurotrophic factor (BDNF) is the endogenous signal that induces Egr3 expression via a PKC/MAPK-dependent pathway. Taken together with the fact that blockade of tyrosine kinase (Trk) neurotrophin receptors reduces basal GABRA4 promoter activity by 50%, our findings support a role for BDNF as the mediator of Egr3-induced GABRA4 regulation in developing neurons and epilepsy and, moreover, suggest that BDNF may alter inhibitory processing in the brain by regulating the balance between phasic and tonic inhibition. |
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Bibliography: | http://www.jbc.org/ |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.C600167200 |