Enhancement of Long-Term Potentiation by a Potent Nitric Oxide-Guanylyl Cyclase Activator, 3-(5-Hydroxymethyl-2-furyl)-1-benzyl-indazole

Abstract

Nitric oxide (NO) is known to affect synaptic plasticity in various regions of the brain via the cGMP-cGMP-dependent protein kinase (PKG) pathway. We found that a novel compound 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole (YC-1), a drug known to modulate the response of soluble guanylyl cyclase to NO, greatly potentiates long-term potentiation (LTP). This compound markedly enhanced the induction of LTP in rat hippocampal and amygdala slices by weak tetanic stimulation. The potentiation of LTP by YC-1 was greatly reduced by NO synthase inhibitor N G -nitro-L-arginine-methylester, guanylyl cyclase inhibitor 1 H-[1,2,4]-oxadiazolo(4,3-a)-quinoxalin-1-one, and PKG inhibitor (9S,10R,12R)-2,3,9,10,11,12, hexahydro-10-methoxy-2,9-dimethyl-1-ox0 -9.12-epoxy-1H-diindolo[1,2,3-fg:3Ј,2Ј,1Ј-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT5823). In addition, mitogen-activated protein kinase kinase inhibitor 2Ј-amino-3Ј-methoxyflavone (PD98059) also markedly inhibited LTP potentiating action of YC-1. Intracellular increase of Ca 2ϩ concentration derived from N-methyl-D-aspartate and glutamate metabotropic receptors contributes to the potentiating action of YC-1. Concurrent perfusion of YC-1 and NO donor sodium nitroprusside for a short time period resulted in the induction of LTP by stimuli at a frequency as low as 0.02 Hz. Incubation of unstimulated hippocampal slices with YC-1 plus nitroprusside increased the immunofluorescence of phosphoextracellular signal-regulated kinase (ERK) and phospho-cAMP response element binding protein (CREB). Furthermore, the Western blot shows that the phosphorylation of ERKs 1 and 2 and CREB of unstimulated hippocampal slices was increased by YC-1 plus nitroprusside, which was inhibited by KT5823. The NO-cGMP-PKG-ERK signaling pathway thus plays important role in the potentiation of LTP by YC-1.Learning and memory are two of the most intensively studied subjects in neuroscience. Various approaches have been used to understand the underlying cellular and molecular mechanisms. Long-term potentiation (LTP) has been identified as a potential synaptic mechanism in several regions of the brain involved in learning and memory (Abel and Lattal, 2001;Schafe et al., 2001). Schaffer collateral inputs to pyramidal neurons in the hippocampus CA1 region exhibit a form of LTP that critically depends on N-methyl-D-aspartate (NMDA) receptor-mediated Ca 2ϩ influx into the postsynaptic cell (Tsien et al., 1996). It has been suggested that nitric oxide (NO), generated postsynaptically by Ca 2ϩ -calmodulindependent NO synthase (NOS), acts as a retrograde messenger (Son et al., 1996;Wilson et al., 1997). A major target of NO is soluble guanylyl cyclase (sGC), which generates the intracellular second messenger cGMP. Consistent with a functional role of cGMP in the expression of LTP, sGC inhibitors suppress LTP (Zhuo et al., 1994), and membrane-permeable dibutyryl-cGMP partially reverses reduction of LTP by an NOS inhibitor (Haley et al., 1992). It is well known that GMP regulates th...

Cognitive Deficits in Rats after Forebrain Cholinergic Depletion are Reversed by a Novel NO Mimetic Nitrate Ester

“…NO/cGMP and PKG contribute to CREB phosphorylation, mediated by the ERK cascade, and also possibly in part via the CaMK pathway (Lu et al, 1999). Interestingly, experiments with YC-1, an agent that augments sGC activation, produced an enhancement of LTP in rat hippocampus and amygdala via an NO/cGMP/PKG/ERK pathway culminating in CREB phosphorylation (Chien et al, 2003). In in vitro brain slice experiments, we found that GT1061 increased the levels of pERK in the CA1 region of the hippocampus.…”

Amygdala Gene Expression Correlates of Social Behavior in Monkeys Experiencing Maternal Separation

“…It has been suggested that NO generated postsynaptically by Ca 2ϩ -calmodulin-dependent NO synthase may act as a retrograde messenger and bind to presynaptic guanylate cyclase to produce cGMP-dependent downstream effects, which strengthen the synaptic connection between coordinately firing cells Son et al, 1998). At the level of systems physiology, one critical function of guanylate cyclase is the facilitation of long-term potentiation in the amygdala (Chien et al, 2003). In rat amygdala slice recordings, stimulation of guanylate cyclase by YC-1 leads to enhanced and enduring potentiation of the corticoamygdala pathway, and this potentiation could be eliminated by concomitant inhibition of NO synthase by L-NAME (Chien et al, 2003).…”

“…At the level of systems physiology, one critical function of guanylate cyclase is the facilitation of long-term potentiation in the amygdala (Chien et al, 2003). In rat amygdala slice recordings, stimulation of guanylate cyclase by YC-1 leads to enhanced and enduring potentiation of the corticoamygdala pathway, and this potentiation could be eliminated by concomitant inhibition of NO synthase by L-NAME (Chien et al, 2003). Other studies have shown in vivo that inhibition of NO synthase impairs memory in rats as assessed by the Morris water maze (Holscher et al, 1996), and recently, Chien et al (2005) have tested YC-1 in vivo and found improvements in Morris water maze performance.…”

Nitric Oxide Mimetic Molecules as Therapeutic Agents in Alzheimers Disease

“…NO/cGMP and PKG contribute to CREB phosphorylation, in part mediated by the ERK cascade, but NO via cGMP-dependent or independent mechanisms may also mediate CREB phosphorylation via PKC and the CaMK cascades [13,43,64]. Interestingly, experiments with YC-1 an agent that augments sGC activation, produced an enhancement of LTP in rat hippocampus and amygdala via an NO/cGMP/PKG/ERK pathway culminating in CREB phosphorylation [42].…”

“…Furthermore, the close temporal relationship between activation of the NO/sGC/cGMP signal transduction cascade and improvements in learning and memory suggest a mechanistic link between the two phenomena [40]. Activation of sGC leading to cGMP accumulation will activate PKG that in turn initiates protein phosphorylation cascades leading to activation of transcription regulating factors such as cAMP response element binding protein (CREB), a critical event in both LTP and the establishment of long-term memory [13,42,43].…”