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The Journal of Neuroscience, July 1, 1999, 19(13):5683-5692
Direct Evidence for Biphasic cAMP Responsive Element-Binding
Protein Phosphorylation during Long-Term Potentiation in the Rat
Dentate Gyrus In Vivo
Stefan
Schulz,
Helge
Siemer,
Manfred
Krug, and
Volker
Höllt
Department of Pharmacology and Toxicology, Otto-von-Guericke
University, 39120 Magdeburg, Germany
Phosphorylation of the transcription factor cAMP responsive
element-binding protein (CREB) is thought to play a key role in synaptic plasticity and long-term memory. However, direct evidence for
CREB phosphorylation during hippocampal long-term potentiation (LTP)
in vivo is sparse. Here, we show that, in the intact
animal, CREB is rapidly phosphorylated in response to high-frequency
stimulation but not low-frequency stimulation of the perforant pathway.
CREB phosphorylation occurred in a biphasic manner, with a first peak at 30 min and a second long-lasting peak beginning 2 hr after tetanic
stimulation and lasting for at least 24 hr. Only stimuli that generated
nondecremental LTP promoted a sustained hyperphosphorylation of CREB
but not stimuli that produced decremental LTP. CREB phosphorylation was
specifically triggered in the dentate gyrus, as well as the CA1, but
not the CA3, hippocampal region. Pretreatment with the NMDA receptor
antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]
cyclohepten-5,10-imine maleate completely prevented activation of CREB. Together, we have resolved the spatial and temporal dynamics of CREB phosphorylation during hippocampal LTP, showing that the transcription factor CREB is specifically recruited at two distinct time points in some forms of hippocampal synaptic plasticity in vivo.
Key words:
CREB; phosphorylation; LTP; hippocampus; antibodies; immunocytochemistry
Copyright © 1999 Society for Neuroscience 0270-6474/99/19135683-10$05.00/0
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