Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats

Abstract

ABSTRACTcAMP͞cAMP-dependent protein kinase (PKA) signaling pathway has been recently proposed to participate in both the late phase of long term potentiation in the hippocampus and in the late, protein synthesis-dependent phase of memory formation. Here we report that a late memory consolidation phase of an inhibitory avoidance learning is regulated by an hippocampal cAMP signaling pathway that is activated, at least in part, by D 1 ͞D 5 receptors. Bilateral infusion of SKF 38393 (7.5 g͞side), a D 1 ͞D 5 receptor agonist, into the CA 1 region of the dorsal hippocampus, enhanced retention of a step-down inhibitory avoidance when given 3 or 6 h, but not immediately (0 h) or 9 h, after training. In contrast, full retrograde amnesia was obtained when SCH 23390 (0.5 g͞side), a D 1 ͞D 5 receptor antagonist, was infused into the hippocampus 3 or 6 h after training. Intrahippocampal infusion of 8Br-cAMP (1.25 g͞side), or forskolin (0.5 g͞side), an activator of adenylyl cyclase, enhanced memory when given 3 or 6 h after training. KT5720 (0.5 g͞side), a specific inhibitor of PKA, hindered memory consolidation when given immediately or 3 or 6 h posttraining. Rats submitted to the avoidance task showed learning-specific increases in hippocampal 3 H-SCH 23390 binding and in the endogenous levels of cAMP 3 and 6 h after training. In addition, PKA activity and P-CREB (phosphorylated form of cAMP responsive element binding protein) immunoreactivity increased in the hippocampus immediately and 3 and 6 h after training. Together, these findings suggest that the late phase of memory consolidation of an inhibitory avoidance is modulated cAMP͞PKA signaling pathways in the hippocampus.Memory is a temporally graded process during which new information becomes consolidated and stored (1-3). From mollusks to mammals, memory can be divided into at least two phases: a protein and RNA synthesis-independent phase that lasts minutes to 1-3 h (short term memory) and a protein and RNA synthesisdependent component [long term memory (LTM)] that lasts several hours to days, weeks, or even longer periods (4-7).Recent work in Aplysia (8-10), Drosophila (11, 12), and mouse (13) has clearly demonstrated that cAMP-responsive transcription, mediated by the CREB (cAMP responsive element binding protein) family of proteins, is a crucial step for the establishment of LTM. cAMP-responsive genes participate in the long term facilitation of neurotransmitter release in Aplysia neurons, a model of nonassociative learning (8-10); the overexpression of a CREB repressor isoform blocks the formation of LTM for a Pavlovian odor avoidance task in Drosophila (11) whereas it does not affect a consolidated, protein synthesis-independent form of memory (7), and, more importantly, transgenic flies expressing an activating isoform of CREB showed an enhancement of LTM (12); in CREB knockout mice, LTM of fear conditioning and spatial learning is disrupted whereas acquisition and short term memory, which lasts 30-60 minutes, are normal (13). Taken together, these findings st...

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