A novel role for cyclic guanosine 3′,5′monophosphate signaling in synaptic plasticity: A selective suppressor of protein kinase A-dependent forms of long-term potentiation

Abstract

At excitatory synapses onto hippocampal CA1 pyramidal cells, activation of cyclic AMP-dependent protein kinase and subsequent down-regulation of protein phosphatases has a crucial role in the induction of long-term potentiation by low-frequency patterns of synaptic stimulation. Because the second messenger cyclic guanosine 3′,5′monophosphate can regulate the activity of different forms of the cyclic AMP degrading enzyme phosphodiesterase, we examined whether increases in cyclic guanosine 3′,5′monophosphate can modulate long-term potentiation induction in the mouse hippocampal CA1 region through effects on cyclic AMP signaling. Using the cyclic guanosine 3′,5′ monophosphate-specific phosphodiesterase inhibitor zaprinast or the nitric oxide donor S-nitroso-D,L-penicillamine to elevate cyclic guanosine 3′,5′monophosphate levels we found that increases in cyclic guanosine 3′,5′monophosphate strongly inhibit the induction of long-term potentiation by lowfrequency patterns of synaptic stimulation where protein kinase A activation is required for longterm potentiation induction. In contrast, zaprinast and S-nitroso-D,L-penicillamine had no effect on the induction of long-term potentiation by high-frequency patterns of synaptic stimulation that induce long-term potentiation in a protein kinase A-independent manner. Directly activating protein kinase A with the phosphodiesterase-resistant cyclic AMP analog 8-Br-cAMP, blocking all phosphodiesterases with 3-isobutyl-1-methylxanthine, or inhibiting protein phosphatases rescued long-term potentiation induction in zaprinast-treated slices. Together, these results suggest that increases in cyclic guanosine 3′,5′monophosphate inhibit long-term potentiation by activating phosphodiesterases that interfere with the protein kinase A-mediated suppression of protein phosphatases needed for long-term potentiation induction. Consistent with the notion that this cyclic guanosine 3′,5′mono-phosphate-mediated inhibitory pathway is recruited by some patterns of synaptic activity, blocking cyclic guanosine 3′,5′monophosphate production strongly facilitated the induction of long-term potentiation by long trains of theta-frequency synaptic stimulation. Together, our results indicate that increases in cyclic guanosine 3′,5′monophosphate can act as a long-term potentiation suppressor mechanism that selectively constrains the induction of protein kinase A-*Corresponding author. Tel: +1-310-206-4654; fax: +1-310-206-5661. E-mail address: todell@mednet.ucla.edu (T. J. O'Dell).. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2007 March 26. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript dependent forms of long-term potentiation induced by low-frequency patterns of synaptic stimulation. Keywordshippocampus; cyclic nucleotides; phosphodiesterase; protein phosphataseThe cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway has a crucial role in learning in animals as diverse as Aplysia, Drosophila, and mammals (Bailey et al....

Spine Expansion and Stabilization Associated with Long-Term Potentiation

“…In addition, baseline synaptic responses were also not altered in cells infused with 8-Br-cAMP (Fig. 5C) (N ϭ 7), consistent with previous studies (Blitzer et al, 1995;Makhinson et al, 2006). To test whether TBP-induced LTP or the associated spine expansion are affected by previous activation of postsynaptic PKA, we loaded pyramidal cells with 8-Br-cAMP for 15-20 min, and then applied TBP.…”

“…7D) (140 Ϯ 15%; N ϭ 54 spines/6 cells; p ϭ 0.95 compared with control spine expansion). It has been suggested that PP1 can be endogenously inactivated by PKA (Kang-Park et al, 2003;Makhinson et al, 2006), and so we would anticipate that persistently elevated PKA activity in the postsynaptic cell would have an effect similar to that of okadaic acid. We tested this possibility by including 8-Br-cAMP in the recording pipette solution, and we repeated the above experiments using LFS.…”

“…Within this time window, LTP can be depotentiated by low-frequency activity (LFS), through a mechanism that requires PP1 (O'Dell et al, 1994;Zhou et al, 2003). PKA can prevent depotentiation by leading to phosphorylation of inhibitor 1, which in turn inhibits PP1 (Kang-Park et al, 2003;Makhinson et al, 2006). To determine whether the consolidation of spine expansion is subject to reversal through mechanisms that are similar to those involved in depotentiation, we examined whether spine expansion is subject to activity-dependent reversal, and if so, whether the same mechanisms are involved in this reversal of spine expansion as in synaptic depotentiation.…”

Inhibition of N-Type Calcium Channels by Activation of GPR35, an Orphan Receptor, Heterologously Expressed in Rat Sympathetic Neurons

“…Therefore, the discovery that zaprinast serves as a relatively potent GPR35 agonist (Taniguchi et al, 2006) affects the interpretation of data in which zaprinast was assumed to solely affect cGMP degradation. For example, zaprinast induced a significant depression of basal synaptic transmission in rat hippocampus attributed to elevation of the intracellular cGMP level (Monfort et al, 2002;Makhinson et al, 2006). However, our data provide evidence for the potential modulation of presynaptic Ca 2ϩ channels by zaprinast acting as a GPR35 agonist.…”

Hippocampal GABAergic Synapses Possess the Molecular Machinery for Retrograde Nitric Oxide Signaling

“…Generation of cGMP by NOsGC appears to be a crucial step in NO signaling in the brain (Boulton et al, 1994;Ahern et al, 2002;Monfort et al, 2004;Makhinson et al, 2006). In subcortical areas, several studies demonstrated that the NO-NOsGC-cGMP pathway can either facilitate (Klyachko et al, 2001;Kraus and Prast, 2002;Li et al, 2004) or inhibit (Ozaki et al, 2000) GABAergic neurotransmission.…”