Phosphorylated cAMP response element-binding protein as a molecular marker of memory processing in rat hippocampus: effect of novelty.
From mollusks to mammals the activation of cAMP response element-binding protein (CREB) appears to be an important step in the formation of long-term memory (LTM). Here we show that a 5 min exposure to a novel environment (open field) 1 hr after acquisition of a one-trial inhibitory avoidance training hinders both the formation of LTM for the avoidance task and the increase in the phosphorylation state of hippocampal Ser 133 CREB [phosphorylated CREB (pCREB)] associated with the avoidance training. To determine whether this LTM deficit is attributable to the reduced pCREB level, rats were bilaterally cannulated to deliver Sp-adenosine 3', 5'-cyclic monophosphothioate (Sp-cAMPS), an activator of PKA. Infusion of Sp-Adenosine 3',5'-cyclic monophosphothioate Sp-cAMPS to CA1 region increased hippocampal pCREB levels and restored normal LTM of avoidance learning in rats exposed to novelty. Moreover, a 5 min exposure to the open field 10 min before the avoidance training interferes with the amnesic effect of a second 5 min exposure to the open field 1 hr after avoidance training and restores the hippocampal levels of pCREB. In contrast, the avoidance training-associated activation of extracellular signal-regulated kinases (p42 and p44 mitogen-activated protein kinases) in the hippocampus is not altered by novelty. Together, these findings suggest that novelty regulates LTM formation by modulating the phosphorylation state of CREB in the hippocampus.
Viola
H
H
Instituto de Biologia Celular y Neurociencias, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 3, 1121 Buenos Aires, Argentina.
Furman
M
M
Izquierdo
L A
LA
Alonso
M
M
Barros
D M
DM
de Souza
M M
MM
Izquierdo
I
I
Medina
J H
JH
D000648:Amnesia, Retrograde / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers; D000242:Cyclic AMP / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007263:Infusions, Parenteral; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008845:Microinjections; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012153:Retention, Psychology / Q000187:drug effects / Q000502:physiology; D013873:Thionucleotides / Q000008:administration & dosage; D013995:Time
D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases