Applying 8-pCPT during this weak tetanus did not change the initial amount of potentiation generated (mean fEPSP slopes were 219

Applying 8-pCPT during this weak tetanus did not change the initial amount of potentiation generated (mean fEPSP slopes were 219.5 13.4% and 224.6 14.9% for control and 8-pCPTCtreated slices, respectively, 2 min after 1 100 Hz stimulation; > 0.5; Fig. of hippocampus- dependent long-term memories. Hippocampal area CA1 is crucial for long-term memory (LTM) formation in mice and humans (Zola-Morgan et al. 1986; Tsien et al. 1996). CA1 synapses express persistent alterations in synaptic strength that are thought to underlie memory storage (Bliss and Collingridge 1993; Moser et al. 1998; Abraham et al. 2002; Lynch 2004). Increases (long-term potentiation [LTP]) or decreases (long-term depression [LTD]) in synaptic strength are mediated by complex interactions of intracellular signaling molecules (Sanes and Lichtman 1999; Braunewell and Manahan-Vaughan 2001). 3,5-Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that is strongly implicated in hippocampal synaptic plasticity and memory. For instance, genetic elimination of calcium/calmodulin-stimulated adenylyl cyclases (AC1 and AC8) blocks late phase-LTP (L-LTP) and LTM for contextual and passive avoidance conditioning (Wong et al. 1999). Similarly, stimulation of cAMP signaling in area CA1 initiates L-LTP (Frey et al. 1993). Although cAMP-dependent protein kinase (PKA) is typically the primary downstream effector of cAMP, cAMP-regulated guanine exchange factors (GEFs) known as Epacs (exchange proteins directly activated by cAMP) also bind cAMP to diversify its signaling influence. Epacs are expressed in the nervous system (Kawasaki et al. 1998), and they bind cAMP to activate a GTPase, Rap, in a PKA-independent fashion (de Rooij et al. 1998). Because Rap can interact with the Ras/ERK cascade, Epacs can modulate ERK-dependent processes in various eukaryotic cells (Lin et al. 2003; Keiper et al. 2004; Johnson-Farley HI TOPK 032 et al. 2005; Traver et al. 2006). In the hippocampus, ERK is required for many forms of synaptic plasticity (Sweatt 2004) and can regulate protein synthesis during long-lasting LTP and LTD via phosphorylation of translation initiation factor eIF4E (Banko et al. 2004, 2006; Kelleher et al. 2004; Schmitt et al. 2005). Given the importance of cAMP and ERK signaling in the hippocampus, it is possible that activation of Epac may critically regulate LTP in this brain region as well. However, it is unknown whether activation of Epac can influence hippocampal synaptic plasticity. We show here that acute perfusion of mouse hippocampal slices with a specific agonist of Epac, 8-(4-chlorophenylthio)-2-O-methyl-cAMP (8-pCPT), enhances the maintenance of LTP in a frequency-dependent manner without affecting basal synaptic transmission or initial LTP induction. This enhancement of LTP stability requires protein synthesis and activation of ERK, but not transcription. Furthermore, application of 8-pCPT leads to a transient increase in phospho-ERK immunoreactivity in hippocampal area CA1. Our data reveal that activation of Epac facilitates LTP in a hippocampal subregion known to be important for the formation of LTMs (Zola-Morgan et al. 1986). Results 8-pCPT does not alter basal synaptic properties in area HI TOPK 032 Kdr CA1 of the hippocampus As a preliminary step toward characterizing the effects of 8-pCPT in area CA1 HI TOPK 032 of the hippocampus, we examined basal synaptic function. The relationship between the presynaptic fiber volley and the fEPSP slope was determined over a range of stimulus intensities as a measure of synaptic responsiveness. We observed no differences between these input-output (I/O) properties in 8-pCPTCtreated slices and ACSF-treated control slices (8-pCPT, = 4.9= 4.7> 0.2; Fig. 1A), indicating that 8-pCPT does not significantly alter basal synaptic transmission. Open in a separate window Figure 1. 8-pCPT does not alter neuronal excitability or presynaptic transmitter release capabilities. (= 12) and control slices (= 15). (= 13) exhibited facilitation similar to controls (= 16) at interpulse intervals of 50, 100, 150, and 200 msec. Paired-pulse facilitation (PPF), a short-lasting presynaptic form of synaptic plasticity and widely used method to infer changes in probability of transmitter release, was not significantly altered by application of 8-pCPT. No significant differences in PPF were observed between ACSF-treated control slices and 8-pCPT-treated slices at 50-, 100-, 150-, or 200-msec interpulse intervals (> 0.2) (Fig. 1B). As such, application HI TOPK 032 of 8-pCPT does not alter basal synaptic properties in hippocampal area CA1. 8-pCPT enhances LTP maintenance, without affecting LTP induction or basal synaptic transmission To address whether activation of Epac by 8-pCPT alters long-lasting forms of plasticity, we investigated its effects on LTP induction and maintenance. First, we found that application of 8-pCPT (100 M) to hippocampal slices during baseline.

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