PMID- 12163549
OWN - NLM
STAT- MEDLINE
DCOM- 20020923
LR  - 20171213
IS  - 0022-3077 (Print)
IS  - 0022-3077 (Linking)
VI  - 88
IP  - 2
DP  - 2002 Aug
TI  - Excitatory actions of GABA increase BDNF expression via a MAPK-CREB-dependent 
      mechanism--a positive feedback circuit in developing neurons.
PG  - 1005-15
AB  - During early neuronal development, GABA functions as an excitatory 
      neurotransmitter, triggering membrane depolarization, action potentials, and the 
      opening of plasma membrane Ca(2+) channels. These excitatory actions of GABA lead 
      to a number of changes in neuronal structure and function. Although the effects 
      of GABA on membrane biophysics during early development have been well 
      documented, little work has been done to examine the possible mechanisms 
      underlying GABA-regulated plastic changes in the developing brain. This study 
      focuses on GABA-regulated kinase activity and transcriptional control. We 
      utilized a combination of Western blotting and immunocytochemical techniques to 
      examine two potential downstream pathways regulated by GABA excitation: the 
      p42/44 mitogen-activated protein kinase (MAPK) cascade and the transcription 
      factor cyclic AMP response element binding protein (CREB). During early 
      development of cultured hypothalamic neurons (5 days in vitro), stimulation with 
      GABA triggered activation of the MAPK cascade and phosphorylation of CREB at Ser 
      133. These effects were mediated by the GABA(A) receptor, since administration of 
      the GABA(A) receptor-specific agonist muscimol (50 microM) triggered pathway 
      activation, and pretreatment with the GABA(A)-receptor specific antagonist 
      bicuculline (20 microM) blocked pathway activation. Immunocytochemistry revealed 
      a spatial and temporal correlation between activation of the MAPK cascade and 
      CREB phosphorylation. Pretreatment with the MAPK/ERK kinase (MEK) inhibitor U0126 
      (10 microM) attenuated CREB phosphorylation, indicating that the MAPK pathway 
      regulates that activation state of CREB. In contrast to the excitatory effects 
      observed during early development, in more mature neurons, GABA functions as an 
      inhibitory transmitter. Consistent with this observation, GABA(A) receptor 
      activation did not stimulate MAPK cascade activation or CREB phosphorylation in 
      mature cultures (18 days in vitro). To determine whether GABA(A) receptor 
      activation during early development stimulates gene expression, we examined the 
      inducible expression of the neurotrophin brain-derived neurotrophic factor 
      (BDNF). Both GABA and muscimol stimulated BDNF expression, and pretreatment with 
      U0126 attenuated GABA-induced BDNF expression. Whole cell electrophysiological 
      recording was used to assess the effects of BDNF on GABA release. BDNF (100 
      ng/ml) dramatically increased the frequency of excitatory GABAergic spontaneous 
      postsynaptic currents. Together, these data suggest a positive excitatory 
      feedback loop between GABA and BDNF expression during early development, where 
      GABA facilitates BDNF expression, and BDNF facilitates the synaptic release of 
      GABA. Signaling via the MAPK cascade and the transcription factor CREB appear to 
      play a substantial role in this process.
FAU - Obrietan, Karl
AU  - Obrietan K
AD  - Department of Neuroscience, The Ohio State University, Columbus 43210, USA. 
      obrietan.1@osu.edu
FAU - Gao, Xiao-Bing
AU  - Gao XB
FAU - Van Den Pol, Anthony N
AU  - Van Den Pol AN
LA  - eng
GR  - NS-34887/NS/NINDS NIH HHS/United States
GR  - NS-41454/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Neurophysiol
JT  - Journal of neurophysiology
JID - 0375404
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (GABA Agonists)
RN  - 0 (GABA Antagonists)
RN  - 0 (Receptors, GABA-A)
RN  - 2763-96-4 (Muscimol)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - SY7Q814VUP (Calcium)
RN  - Y37615DVKC (Bicuculline)
SB  - IM
MH  - Animals
MH  - Bicuculline/pharmacology
MH  - Blotting, Western
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Calcium/metabolism
MH  - Cell Culture Techniques
MH  - Cyclic AMP Response Element-Binding Protein/*metabolism
MH  - GABA Agonists/pharmacology
MH  - GABA Antagonists/pharmacology
MH  - Hypothalamus/cytology/*growth & development/*metabolism
MH  - Immunohistochemistry
MH  - Microscopy, Fluorescence
MH  - Mitogen-Activated Protein Kinase Kinases/*metabolism
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Muscimol/pharmacology
MH  - Nerve Growth Factor/metabolism
MH  - Neurons/metabolism
MH  - Patch-Clamp Techniques
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, GABA-A/metabolism
MH  - Signal Transduction
MH  - gamma-Aminobutyric Acid/*metabolism
EDAT- 2002/08/07 10:00
MHDA- 2002/09/24 06:00
CRDT- 2002/08/07 10:00
PHST- 2002/08/07 10:00 [pubmed]
PHST- 2002/09/24 06:00 [medline]
PHST- 2002/08/07 10:00 [entrez]
AID - 10.1152/jn.2002.88.2.1005 [doi]
PST - ppublish
SO  - J Neurophysiol. 2002 Aug;88(2):1005-15. doi: 10.1152/jn.2002.88.2.1005.