Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins.
To examine the role of C/EBP-related transcription factors in long-term synaptic plasticity and memory storage, we have used the tetracycline-regulated system and expressed in the forebrain of mice a broad dominant-negative inhibitor of C/EBP (EGFP-AZIP), which preferentially interacts with several inhibiting isoforms of C/EBP. EGFP-AZIP also reduces the expression of ATF4, a distant member of the C/EBP family of transcription factors that is homologous to the Aplysia memory suppressor gene ApCREB-2. Consistent with the removal of inhibitory constraints on transcription, we find an increase in the pattern of gene transcripts in the hippocampus of EGFP-AZIP transgenic mice and both a reversibly enhanced hippocampal-based spatial memory and LTP. These results suggest that several proteins within the C/EBP family including ATF4 (CREB-2) act to constrain long-term synaptic changes and memory formation. Relief of this inhibition lowers the threshold for hippocampal-dependent long-term synaptic potentiation and memory storage in mice.
Chen
Amy
A
Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Muzzio
Isabel A
IA
Malleret
Gaël
G
Bartsch
Dusan
D
Verbitsky
Miguel
M
Pavlidis
Paul
P
Yonan
Amanda L
AL
Vronskaya
Svetlana
S
Grody
Michael B
MB
Cepeda
Ivan
I
Gilliam
T Conrad
TC
Kandel
Eric R
ER
D051701:Activating Transcription Factor 4; D000818:Animals; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D004594:Electrophysiology; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017774:Long-Term Potentiation / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D009924:Organ Culture Techniques; D016716:PC12 Cells; D025341:Principal Component Analysis; D051381:Rats; D013569:Synapses / Q000502:physiology*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics
C497110:Atf4 protein, rat; D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; C497251:Ddit3 protein, rat; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP