Transgenic mice expressing an inhibitory truncated form of p300 exhibit long-term memory deficits.
The formation of many forms of long-term memory requires several molecular mechanisms including regulation of gene expression. The mechanisms directing transcription require not only activation of individual transcription factors but also recruitment of transcriptional coactivators. CBP and p300 are transcriptional coactivators that interact with a large number of transcription factors and regulate transcription through multiple mechanisms, including an intrinsic histone acetyltransferase (HAT) activity. HAT activity mediates acetylation of lysine residues on the amino-terminal tails of histone proteins, thereby increasing DNA accessibility for transcription factors to activate gene expression. CBP has been shown to play an important role in long-term memory formation. We have investigated whether p300 is also required for certain forms of memory. p300 shares a high degree of homology with CBP and has been shown to interact with transcription factors known to be critical for long-term memory formation. Here we demonstrate that conditional transgenic mice expressing an inhibitory truncated form of p300 (p300Delta1), which lacks the carboxy-terminal HAT and activation domains, have impaired long-term recognition memory and contextual fear memory. Thus, our study demonstrates that p300 is required for certain forms of memory and that the HAT and carboxy-terminal domains play a critical role.
Oliveira
Ana M M
AM
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Wood
Marcelo A
MA
McDonough
Conor B
CB
Abel
Ted
T
D000679:Amygdala / Q000737:chemistry / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000737:chemistry / Q000502:physiology; D002540:Cerebral Cortex / Q000737:chemistry / Q000502:physiology; D003463:Cues; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology; D051548:Histone Acetyltransferases / Q000502:physiology; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017434:Protein Structure, Tertiary; D011930:Reaction Time; D021641:Recognition, Psychology / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014158:Transcription, Genetic
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C494361:Ep300 protein, mouse; D051548:Histone Acetyltransferases; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D004318:Doxycycline