Rapid Increase in Clusters of Presynaptic Proteins at Onset of Long-Lasting Potentiation

Antonova, I. V.; Arancio, Ottavio; Trillat, Anne-Cécile; Wang, Honggang; Zablow, Leonard; Udo, Hiroshi; Kandel, Eric R.; Hawkins, Robert D.

doi:10.1126/science.1066273

Cited by 152 publications

(147 citation statements)

References 27 publications

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“…One other possibility is that cGK may act synergistically with Ca 2ϩ that enters the presynaptic terminal during the weak tetanus, perhaps by converging on a common molecular target. Consistent with that possibility, Antonova et al (2000) recently found that the NO-cGMP-cGK pathway contributes to an increase in the number of synaptophysin-and synapsin-immunoreactive presynaptic terminals during long-lasting potentiation in hippocampal cell culture. Those results provide independent evidence that cGK acts presynaptically and indicate that it in some way affects vesicleassociated proteins.…”

Section: Discussionmentioning

confidence: 52%

Presynaptic Role of cGMP-Dependent Protein Kinase during Long-Lasting Potentiation

et al. 2001

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Previous research has suggested that cGMP-dependent protein kinases (cGKs) may play a role in long-term potentiation in hippocampus, but their site of action has been unknown. We examined this question at synapses between pairs of hippocampal neurons in dissociated cell culture. Injection of a specific peptide inhibitor of cGK into the presynaptic but not the postsynaptic neuron blocked long-lasting potentiation induced by tetanic stimulation of the presynaptic neuron. As controls, injection of a scrambled peptide or a peptide inhibitor of cAMP-dependent protein kinase into either neuron did not block potentiation. Conversely, injection of the ␣ isozyme of cGK type I into the presynaptic but not the postsynaptic neuron produced activity-dependent potentiation that did not require NMDA receptor activation. Evidence from Western blots, reverse transcription-PCR, activity assays, and immunocytochemistry indicates that endogenous cGK type I is present in the neurons, including presynaptic terminals. These results support the idea that cGK plays an important presynaptic role during the induction of long-lasting potentiation in hippocampal neurons.

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Section: Discussionmentioning

confidence: 52%

Presynaptic Role of cGMP-Dependent Protein Kinase during Long-Lasting Potentiation

et al. 2001

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“…Glutamate is the major excitatory neurotransmitter in the hippocampus and mediates the neuronal response through CREB activation and LTP formation, eventually leading to synapse development and strengthening. In vitro studies on cultured hippocampal neurons (14,15) have used brief glutamate stimuli to investigate the biochemical changes that underlie synaptic strength modification. We found that cultures pretreated for 2 h with 5 M A␤ showed a 40-45% decrease in CREB phosphorylation in response to treatment with 50 M glutamate for 15 min (Fig.…”

Section: Resultsmentioning

confidence: 99%

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Vitolo

Sant’Angelo

Costanzo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Changes in hippocampal function seem critical for cognitive impairment in Alzheimer's disease (AD). Although there is eventual loss of synapses in both AD and animal models of AD, deficits in spatial memory and inhibition of long-term potentiation (LTP) precede morphological alterations in the models, suggesting earlier biochemical changes in the disease. In the studies reported here we demonstrate that amyloid ␤-peptide (A␤) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAII␣. Consistent with this, CREB phosphorylation in response to glutamate is decreased, and the decrease is reversed by rolipram, a phosphodiesterase inhibitor that raises cAMP and leads to the dissociation of the PKA catalytic and regulatory subunits. It is likely that a similar mechanism underlies 〈␤ inhibition of LTP, because rolipram and forskolin, agents that enhance the cAMP-signaling pathway, can reverse this inhibition. This reversal is blocked by H89, an inhibitor of PKA. These observations suggest that 〈␤ acts directly on the pathways involved in the formation of late LTP and agents that enhance the cAMP͞PKA͞CREB-signaling pathway have potential for the treatment of AD. A lzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by mild cognitive impairment at its onset and deficits in multiple cortical functions in later stages. To date, the vast majority of its symptoms have been attributed to the loss of synapses and the death of neurons that occur in the course of the disease. The overproduction and accumulation of the amyloid ␤-peptide (A␤) and particularly its 42-aa form (A␤ 1-42 ) have been shown to play a crucial role in both of these processes in animal models of AD (1, 2). Although these phenomena can account for the late debilitating stages of the disease, the mechanisms by which A␤ causes early cognitive and behavioral changes remain a matter of conjecture. Recent studies on animal models of AD have highlighted the discrepancy between behavioral deficits and neuropathological findings. Electrophysiological studies on mice that overexpress A␤ show impairment of long-term potentiation (LTP) that does not correlate with the extent of synaptic loss, amyloid deposition, or cell death (3-5). In addition, animals without detectable accumulation of A␤ have been reported to have behavioral deficits (6, 7). While examining gene expression in nerve growth factorprimed PC12 cells that had been exposed to A␤ 1-42 for 3 h, we observed that a group of genes including CREB2 (ATF4) and ubiquitin C-terminal hydrolase, which have been implicated in the switch from early to late LTP, were regulated in a manner consistent with an 〈␤-mediated inhibition of the cAMPmediated signaling pathway for the consolidation of LTP. ʈ The details of the biochemical pathway mediating the switch from early to late LTP have been worked out in aplysia and mice (8) and depend on the activation of the transcription factor CREB by phosphorylat...

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“…However, in clinical practice most patients who achieve an initial response to antibody treatment generally acquire resistance within 1 year [6]. HER-2 transmits information from breast cancer cell surface into cytoplasm and is crucial in growth inhibition and cellular adhesion [7]. Breast cancer cells overexpressing HER-2 and CD44 receptors tend to be much more elastic than normal cells, as they exhibit a much stiffer extracellular matrix (ECM) [8].…”

Section: Introductionmentioning

confidence: 99%

Combined treatment of human MCF-7 breast carcinoma with antibody, cationic lipid and hyaluronic acid using ex vivo assays

Bartusik

Tomanek

Lattová

et al. 2010

Journal of Pharmaceutical and Biomedical Analysis

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Rapid Increase in Clusters of Presynaptic Proteins at Onset of Long-Lasting Potentiation

Cited by 152 publications

References 27 publications

Presynaptic Role of cGMP-Dependent Protein Kinase during Long-Lasting Potentiation

Presynaptic Role of cGMP-Dependent Protein Kinase during Long-Lasting Potentiation

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Combined treatment of human MCF-7 breast carcinoma with antibody, cationic lipid and hyaluronic acid using ex vivo assays

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