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...

The hippocampus and amygdala, the entorhinal cortex and the parietal cortex participate, in that sequence, both in the formation and in the expression of memory for a step-down inhibitory avoidance task in rats. Bilateral infusion of AP5 or muscimol caused retrograde amnesia when given 0 min after training into both hippocampus and amygdala, when given or 180 min after training into the entorhinal cortex, or when given 180 min after training into the parietal cortex. Therefore, memory formation requires the sequential and integrated activity of all these areas mediated by glutamate NMDA receptors in each case. Pre-test administration of CNQX 1 day after training into hippocampus and amygdala, 1 or 31 days after training in entorhinal cortex, or 1, 31 or 60 days after training in the parietal cortex temporarily blocked retention test performance. Therefore, 1 day after training, all these brain structures are necessary for retrieval; 1 month later, the hippocampus and amygdala are no longer necessary for retrieval but the entorhinal and parietal cortex still are; and 60 days after training only the parietal cortex is needed. In all cases the mechanisms of retrieval require intact glutamate AMPA receptors.

No abstract

No abstract

Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), which is thought to be a retrograde messenger in long-term potentiation (LTP), enhances glutamate release and LTP through an action on presynaptic nerve endings. The PAF antagonist BN 52021 blocks CAI LTP in hippocampal slices, and, when infused into rat dorsal hippocampus pre-or posttraining, blocks retention of inhibitory avoidance. Here we report that memory is affected by pre-or posttraining infusion of the PAF analog 1-O-hexadecyl-2-N-methylcarbamoyl-sn-glycero-3-phosphocholine (mc-PAF) into either rat dorsal hippocampus, amygdala, or entorhinal cortex. Male Wistar rats were implanted bilaterally with cannulae in these brain regions. After recovery from surgery, the animals were trained in step-down inhibitory avoidance or in a spatial habituation task and tested for retention 24 h later. mc-PAF (1.0 ,ug per side) enhanced retention test performance of the two tasks when infused into the hippocampus before training without altering training session performance. In addition, mc-PAF enhanced retention test performance of the avoidance task when infused into (i) the hippocampus 0 but not 60 min after training; (ii) the amygdala immediately after training; and (iii) the entorhinal cortex 100 but not 0 or 300 min after training. In confirmation of previous findings, BN 52021 (0.5 ,lg per side) was found to be amnestic for the avoidance task when infused into the hippocampus or the amygdala immediately but not 30 or more minutes after training or into the entorhinal cortex 100 but not 0 or 300 min after training. These findings support the hypothesis that memory involves PAF-regulated events, possibly LTP, generated at the time of training in hippocampus and amygdala and 100 min later in the entorhinal cortex.Learning and memory probably involve activity-dependent modifications of synaptic efficiency (1, 2). Although this concept of synaptic plasticity in information storage originated from the century-old work of Santiago Ramon y Cajal, the cellular and molecular events underlying memory and learning are not clearly understood.LTP (long-term potentiation) is a model of activitydependent synaptic plasticity (1) and is a candidate mechanism for certain forms of memory in the mammalian brain (3). LTP is a persistent enhancement of excitatory neurotransmission that results from high-frequency activation of hippocampal synapses as well as of other brain regions (1,4). Activitydependent potentiation involves the N-methyl-D-aspartate