Genetic Demonstration of a Role for PKA in the Late Phase of LTP and in Hippocampus-Based Long-Term Memory

Abel, Ted; Nguyen, Peter V.; Barad, Mark; Deuel, Thomas A.S; Kandel, Eric R.; Bourtchouladze, Rusiko

doi:10.1016/s0092-8674(00)81904-2

Cited by 1,137 publications

(1,035 citation statements)

References 38 publications

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“…AMYGFamygdala; CPuFcaudate putamen; HIPPFhippocampus; IC/SCFinferior/superior colliculus; NAccFnucleus accumbens; PnCFpontine reticular nucleus; PPTNFpedunculopontine tegmental nucleus; SMNFspinal motoneurons; VPFventral pallidum; and VTAFventral tegmental area. Houslay and Adams, 2003;Rochais et al, 2004), we tested the effects of crossing Gas* transgenic mice to another line of transgenic mice expressing the PKA inhibitor R(AB) (Abel et al, 1997). Together, our results show that Gas* expression results in a complex, brainregion-specific biochemical response that ultimately leads to deficits in PPI.…”

Section: Introductionmentioning

confidence: 91%

“…This transgene is expressed in addition to the endogenous genomic copy of Gas, which we have verified remains functional (as indicated by increased adenylyl cyclase activity in response to GTPgS stimulation; data not shown). As described previously (Abel et al, 1997), R(AB) mice express a dominant-negative regulatory subunit for PKA, resulting in inhibited PKA activity. Expression of both the Gas* and R(AB) transgenes are driven by the CaMKIIa promoter, which restricts expression to postnatal forebrain neurons (see Figure 1b for expression pattern).…”

Section: Subjectsmentioning

confidence: 99%

“…Expression of both the Gas* and R(AB) transgenes are driven by the CaMKIIa promoter, which restricts expression to postnatal forebrain neurons (see Figure 1b for expression pattern). Animals were genotyped by Southern blot using a transgene-specific probe as described (Abel et al, 1997); however, all experiments were conducted by personnel blind to genotype. For experiments employing C57BL/6J mice, 2 to 5-month-old male and female subjects were either bred inhouse or were obtained from Jackson Laboratories and group housed in our breeding facilities for a minimum of 1 week before testing.…”

Section: Subjectsmentioning

confidence: 99%

“…To block PKA signaling within forebrain neurons, and potentially the pathway to cAMP PDE upregulation, we crossed the Gas* transgenic mice to R(AB) transgenic mice (Abel et al, 1997). Expression of both the Gas* and R(AB) transgenes within forebrain neurons increases PPI across trials, relative to expression of only Gas* (effect of genotype: F (3,48) ¼ 6.85, po0.002; post hoc Gas* vs WT, R(AB), and Gas* Â R(AB), po0.02-0.002; Figure 6).…”

Section: Ppi Deficits Of Gas* Transgenic Mice Are Rescued By Camp Pdementioning

confidence: 99%

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Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

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Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Gas (Gas*) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Gas* causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Gas* increases cAMP levels in the striatum. Suprisingly, however, Gas* mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Gas* on PPI because Rp-cAMPS decreases PPI in C57BL/ 6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Gas* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Gas* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Gas* mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Gas*. We conclude that expression of Gas* within forebrain neurons causes PPI deficits because of a PKAdependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

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Section: Introductionmentioning

confidence: 91%

Section: Subjectsmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

Section: Ppi Deficits Of Gas* Transgenic Mice Are Rescued By Camp Pdementioning

confidence: 99%

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Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

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“…It is usually formed by multiple pairing trials but not by a single trial. It has been demonstrated that the cAMP signaling system plays critical roles in producing LTM, or long-term synaptic plasticity considered to underlie LTM formation, in mammals [1], insects [6,19] and mollusks [2]. In all of these animals, production of cAMP stimulates PKA, and this activates the transcription factor CREB (cAMP element-binding protein).…”

Section: Main Textmentioning

confidence: 99%

Stimulation of the cAMP system by the nitric oxide-cGMP system underlying the formation of long-term memory in an insect

Matsumoto¹,

Hatano²,

Unoki³

et al. 2009

Neuroscience Letters

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The nitric oxide (NO)-cGMP signaling system and cAMP system play critical roles in formation of multiple-trial induced, protein synthesis-dependent long-term memory (LTM) in many vertebrates and invertebrates. The relationship between the NO-cGMP system and cAMP system, however, remains controversial. In honey bees, the two systems have been suggested to converge on protein kinase A (PKA), based on the finding in vitro that cGMP activates PKA when sub-optimal dose of cAMP is present. In crickets, however, we have suggested that NO-cGMP pathway operates on PKA via activation of adenylyl cyclase and production of cAMP for LTM formation. To resolve this issue, we compared the effect of multiple-trial conditioning against the effect of an externally applied cGMP analog for LTM formation in crickets, in the presence of sub-optimal dose of cAMP analog and in condition in which adenylyl cyclase was inhibited. The obtained results suggest that an externally applied cGMP analog activates PKA when sub-optimal dose of cAMP analog is present, as is suggested in honey bees, but cGMP produced by multiple-trial conditioning cannot activate PKA even when sub-optimal dose of cAMP analog is present, thus indicating that cGMP produced by multiple-trial conditioning is not accessible to PKA. We conclude that the NO-cGMP system stimulates the cAMP system for LTM formation. We propose that LTM is formed by an interplay of two classes of neurons, namely, NO-producing neurons regulating LTM formation and NO-receptive neurons that are more directly involved in formation of long-term synaptic plasticity underlying LTM formation.3 Main textRecent studies have suggested that many of the molecular mechanisms underlying learning and memory are conserved among vertebrates and invertebrates, the most convincing evidence for which has been obtained by the study of the mechanisms of the formation of LTM [7]. LTM is defined as a protein synthesis-dependent phase of memory lasting for day to a lifetime. It is usually formed by multiple pairing trials but not by a single trial. It has been demonstrated that the cAMP signaling system plays critical roles in producing LTM, or long-term synaptic plasticity considered to underlie LTM formation, in mammals [1], insects [6,19] and mollusks [2]. In all of these animals, production of cAMP stimulates PKA, and this activates the transcription factor CREB (cAMP element-binding protein). Activation of CREB leads to a protein synthesis-dependent long-term synaptic plasticity that underlies LTM formation [7,20].The NO-cGMP system also plays critical roles in the formation of LTM in mammals [9], honey bees [15,16], crickets [14] and mollusks [8]. NO is a membrane-permeable intercellular signaling molecule produced by NO synthase (NOS).NO diffuses into neighboring cells and stimulates soluble guanylyl cyclase, and produced cGMP plays various physiological roles [5], including induction of LTM in many animals.In crickets, we have reported that the NO-cGMP system and cAMP system play major roles in formatio...

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Plasticity, Hippocampal Place Cells, and Cognitive Maps

Shapiro¹

2001

Arch Neurol

111

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Memory of even the briefest event can last a lifetime. Thus, learning and memory require neuronal mechanisms that allow rapid, yet persistent, changes to brain circuits. Hippocampal neuropsychology, synaptic and cellular electrophysiology, pharmacology, and molecular genetics converge and begin to reveal these mechanisms. Lesions of the hippocampus profoundly impair memory for recent events in humans and rodents. Circuits within the hippocampus are remarkably plastic, and this plasticity is mediated in part through changes in synaptic strength and revealed by long-term potentiation (LTP) and long-term depression (LTD). N-methyl D-aspartate (NMDA) receptors, a subtype of glutamate receptor, are crucial for inducing these plastic changes, and blocking these receptors reduces plasticity and impairs learning in tasks that require the hippocampus. Molecular genetic alterations that disrupt signaling mechanisms downstream of the NMDA receptor also prevent LTP induction and impair hippocampus-dependent learning. N-methyl D-aspartate receptor mechanisms have also been linked to information coding by hippocampal neurons. Hippocampal cells fire selectively in specific and restricted locations (place fields) as rodents move through open environments. Place fields form within minutes and persist for months. N-methyl D-aspartate receptor antagonists prevent the establishment of stable place fields. The same molecular genetic manipulations that interfere with hippocampal NMDA receptor function, prevent LTP induction, and impair spatial learning also disrupt the formation of stable hippocampal place fields. Finally, learning has been improved in mice with genetically modified NMDA receptors that enhance LTP induction. Thus, hippocampal cells "learn" to encode the salient features of experience through NMDA receptor-dependent synaptic plasticity mechanisms, and this rapid and persistent neuronal encoding is a crucial step toward the formation of long-term memory. Disruption of these plasticity mechanisms may underlie age-related memory deficits.

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Genetic Demonstration of a Role for PKA in the Late Phase of LTP and in Hippocampus-Based Long-Term Memory

Cited by 1,137 publications

References 38 publications

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Stimulation of the cAMP system by the nitric oxide-cGMP system underlying the formation of long-term memory in an insect

Plasticity, Hippocampal Place Cells, and Cognitive Maps

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