title: Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins.
abstract: 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.
authors.affiliation: Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Chen
authors.forename: Isabel A
authors.initials: IA
authors.lastname: Muzzio
authors.forename: Gaël
authors.initials: G
authors.lastname: Malleret
authors.forename: Dusan
authors.initials: D
authors.lastname: Bartsch
authors.forename: Miguel
authors.initials: M
authors.lastname: Verbitsky
authors.forename: Paul
authors.initials: P
authors.lastname: Pavlidis
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Yonan
authors.forename: Svetlana
authors.initials: S
authors.lastname: Vronskaya
authors.forename: Michael B
authors.initials: MB
authors.lastname: Grody
authors.forename: Ivan
authors.initials: I
authors.lastname: Cepeda
authors.forename: T Conrad
authors.initials: TC
authors.lastname: Gilliam
authors.forename: Eric R
authors.initials: ER
authors.lastname: Kandel
mesh_terms: 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
chemical_list: 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