Previous studies have revealed that pyramidal neurons in the CA1 region of the hippocampus are extremely susceptible to ischemia-induced cell damage and undergo selective degeneration 2–4 days after ...the insult. Little is known about early morphological changes in neurons occurring immediately after ischemic insult. Using two-photon laser scanning microscopy we monitored dendritic morphology of cells expressing enhanced green fluorescent protein in response to a transient hypoxic–ischemic episode in organotypic hippocampal slice preparations. This type of vital imaging provides direct evidence of dendritic rearrangements in rat CA1 pyramidal neurons occurring as soon as 20 min after oxygen–glucose deprivation. We propose that dendritic reorganization, resembling that occurring after tetanic stimulation, may be an early stage response to compensate the loss of synapses caused by ischemia-induced neuronal injury.
Previous work has shown that mice missing the alpha-isoform of calcium-calmodulin-dependent protein kinase II (alpha-CaMKII) have a deficiency in CA1 hippocampal long-term potentiation (LTP). ...Follow-up studies on subsequent generations of these mutant mice in a novel inbred background by our laboratories have shown that whereas a deficiency in CA1 LTP is still present in alpha-CaMKII mutant mice, it is different both quantitatively and qualitatively from the deficiency first described. Mice of a mixed 129SvOla/SvJ;BALB/c;C57B1/6 background derived from brother/sister mating of the alpha-CaMKII mutant line through multiple generations (>10) were produced by use of in vitro fertilization. Although LTP at 60 min post-tetanus was clearly deficient in these (-/-) alpha-CaMKII mice (42.6%, n = 33) compared with (+/+) alpha-CaMKII control animals (81.7%, n = 17), alpha-CaMKII mutant mice did show a significant level of LTP. The amount of LTP observed in alpha-CaMKII mutants was normally distributed, blocked by APV (2.7%, n = 8), and did not correlate with age. Although this supports a role for alpha-CaMKII in CA1 LTP, it also suggests that a form of alpha-CaMKII-independent LTP is present in mice that could be dependent on another kinase, such as the beta-isoform of CaMKII. A significant difference in input/output curves was also observed between (-/-) alpha-CaMKII and (+/+) alpha-CaMKII animals, suggesting that differences in synaptic transmission may be contributing to the LTP deficit in mutant mice. However, tetani of increasing frequency (50, 100, and 200 Hz) did not reveal a higher threshold for potentiation in (-/-) alpha-CaMKII mice compared with (+/+) alpha-CaMKII controls.
Learning Mechanisms: The Case for CaM-KII Lisman, John; Malenka, Robert C.; Nicoll, Roger A. ...
Science (American Association for the Advancement of Science),
1997-Jun-27, Letnik:
276, Številka:
5321
Journal Article
Recenzirano
Together with previous findings, the findings of Barria et al. provide strong evidence for a simple, postsynaptic mechanism for enhancing synaptic transmission during long-term potentiation.
Beta amyloid (Aβ), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer’s Disease. Recent studies indicate that ...this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Aβ employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Aβ-induced disruption of synaptic structure and function.
Beta amyloid (Abeta), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer's disease. Recent studies indicate that ...this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Abeta employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Abeta-induced modification of synaptic structure and function.
Beta amyloid (Aβ), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer's disease. Recent studies indicate that ...this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Aβ employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Aβ-induced modification of synaptic structure and function.
Long-term potentiation (LTP) of synaptic transmission in the hippocampus is a much-studied example of synaptic plasticity. Although the role of N-methyl-D-aspartate (NMDA) receptors in the induction ...of LTP is well established, the nature of the persistent signal underlying this synaptic enhancement is unclear. Involvement of protein phosphorylation in LTP has been widely proposed, with protein kinase C (PKC) and calcium-calmodulin kinase type II (CaMKII) as leading candidates. Here we test whether the persistent signal in LTP is an enduring phosphoester bond, a long-lived kinase activator, or a constitutively active protein kinase by using H-7, which inhibits activated protein kinases and sphingosine, which competes with activators of PKC (ref. 17) and CaMKII (ref. 18). H-7 suppressed established LTP, indicating that the synaptic potentiation is sustained by persistent protein kinase activity rather than a stably phosphorylated substrate. In contrast, sphingosine did not inhibit established LTP, although it was effective when applied before tetanic stimulation. This suggests that persistent kinase activity is not maintained by a long-lived activator, but is effectively constitutive. Surprisingly, the H-7 block of LTP was reversible; evidently, the kinase directly underlying LTP remains activated even though its catalytic activity is interrupted indicating that such kinase activity does not sustain itself simply through continual autophosphorylation (see refs 9, 13, 15).
In this study we examine developmental changes between postnatal day (PND) 4 and 14 in synaptic transmission and plasticity in the CA1 region of hippocampal slices. We confirm previous results that ...tetanus-induced long-term potentiation (LTP) in field recordings is diminished in slices from younger animals. LTP in whole-cell current-clamp recordings is also diminished in younger animals. However, robust LTP can be induced in young animals if sufficient postsynaptic depolarization is provided during LTP induction. Furthermore, we find differences in synaptic transmission between PND 4 and 14, suggesting that the depolarization during tetanic stimulation in young tissue is ineffective to produce LTP. These results indicate that the smaller potentiation in field recordings in slices from younger animals is attributable to insufficient postsynaptic depolarization during LTP induction rather than a defect in expression mechanisms.
AMPA Receptor Trafficking and GluR1 Seth G. N. Grant; Malinow, Roberto; Rumpel, Simon ...
Science (American Association for the Advancement of Science),
10/2005, Letnik:
310, Številka:
5746
Journal Article
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