Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 16, Issue 10, Pages 1871-1876Publisher
WILEY
DOI: 10.1046/j.1460-9568.2002.02260.x
Keywords
cAMP-dependent protein kinase; hippocampus; LTP; protein phosphatases; synaptic plasticity; transgenic mice
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Funding
- NIA NIH HHS [AG18199] Funding Source: Medline
- NICHD NIH HHS [HD26979] Funding Source: Medline
- NIMH NIH HHS [MH60244] Funding Source: Medline
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Protein kinases and phosphatases play antagonistic roles in regulating hippocampal long-term potentiation (LTP), with kinase inhibition and phosphatase activation both impairing LTP. The late phase of LTP (L-LTP) requires activation of cAMP-dependent protein kinase (PKA) for its full expression. One way in which PKA may critically modulate L-LTP is by relieving an inhibitory constraint imposed by protein phosphatases. Using mutant PKA mice [R(AB) transgenic mice] that have genetically reduced hippocampal PKA activity, we show that dercient L-LTP in area CA1 of mutant hippocampal slices is rescued by acute application of two inhibitors of protein phosphatase-1 and protein phosphatase-2A (PP1/2A) (okadaic acid and calyculin A). Furthermore, synaptic facilitation induced by forskolin, an adenylyl cyclase activator, was impaired in R(AB) transgenics and was also rescued by a PP1/2A inhibitor in mutant slices. Inhibition of PP1/2A did not affect early LTP (E-LTP) or basal synaptic transmission in mutant and wildtype slices. Our data show that genetic inhibition of PKA impairs L-LTP by reducing PKA-mediated suppression of PP1/2A.
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