Synapse‐specific protein kinase C activation enhances maintenance of long‐term potentiation in rat hippocampus.

1. Protein kinase C (PKC) stimulators, 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA) or cis‐unsaturated fatty acid (UFA), have been shown to prolong synaptic enhancement induced by long‐term potentiation (LTP). This observation suggests a role for PKC in the biochemical mechanisms underlying maintained enhancement. 2. To determine if PKC stimulators prolong LTP by acting selectively at synapses given high‐frequency stimulation or by actions that are not synapse‐specific (e.g. increased postsynaptic excitability) we examined the effect of TPA or UFA on input‐selective enhancement. Population EPSPs, evoked in the same granule cell population by either the medial (MPP) or lateral (LPP) perforant path, can be selectively enhanced leaving the other perforant path input which receives only low‐frequency stimulation as an internal control for PKC stimulator effects not specific to enhanced synapses. 3. Synapse‐specific effects were in fact observed, as UFA or TPA selectively prolonged MPP enhancement following two trains of high‐frequency MPP stimulation, without affecting responses evoked by the LPP. A similar synapse selectivity of PKC stimulator action was seen following high‐frequency LPP stimulation. 4. These findings suggest that PKC stimulators prolong enhancement by acting specifically at high‐frequency‐stimulated synapses. PKC stimulators do not appear to affect either postsynaptic neurone excitability or synapses given only low‐frequency stimulation. This provides further evidence that PKC acts synergistically with the consequences of repetitive synaptic activation to maintain enhancement.

[1]  J. Wood,et al.  Polyclonal antibodies to phospholipid/Ca2+-dependent protein kinase and immunocytochemical localization of the enzyme in rat brain. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Robert C. Malenka,et al.  Phorbol esters enhance transmitter release in rat hippocampal slices , 1987, Brain Research.

[3]  S. Silberberg,et al.  Activation of protein kinase C augments evoked transmitter release , 1987, Nature.

[4]  T. H. Brown,et al.  Conductance mechanism responsible for long-term potentiation in monosynaptic and isolated excitatory synaptic inputs to hippocampus. , 1986, Journal of neurophysiology.

[5]  Robert C. Malenka,et al.  Potentiation of synaptic transmission in the hippocampus by phorbol esters , 1986, Nature.

[6]  D. Lovinger,et al.  Direct relation of long-term synaptic potentiation to phosphorylation of membrane protein F1, a substrate for membrane protein kinase C , 1986, Brain Research.

[7]  A. Routtenberg.  Synaptic plasticity and protein kinase C. , 1986, Progress in brain research.

[8]  J. Neary,et al.  Modulation of ion channels by Ca2+-activated protein phosphorylation: a biochemical mechanism for associative learning. , 1986, Progress in brain research.

[9]  D. Lovinger,et al.  Translocation of protein kinase C activity may mediate hippocampal long-term potentiation. , 1986, Science.

[10]  Bruce L. McNaughton,et al.  A selective increase in phosphorylation of protein F1, a protein kinase C substrate, directly related to three day growth of long term synaptic enhancement , 1985, Brain Research.

[11]  G. Lynch,et al.  Long‐term potentiation and depression of synaptic responses in the rat hippocampus: localization and frequency dependency. , 1978, The Journal of physiology.

[12]  A. Ganong,et al.  Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors , 1984, Brain Research.

[13]  D. Linden,et al.  A newly discovered protein kinase C activator (oleic acid) enhances long-term potentiation in the intact hippocampus , 1986, Brain Research.

[14]  T. Bliss,et al.  Long-term potentiation in the dentate gyrus: induction and increased glutamate release are blocked by d(−)aminophosphonovalerate , 1987, Neuroscience.

[15]  Richard J. Miller.  Protein kinase C: a key regulator of neuronal excitability? , 1986, Trends in Neurosciences.

[16]  C. Cotman,et al.  Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl d-aspartate antagonists , 1986, Neuroscience Letters.

[17]  W. Levy,et al.  Synapses as associative memory elements in the hippocampal formation , 1979, Brain Research.

[18]  B. McNaughton,et al.  Physiological identification and analysis of dentate granule cell responses to stimulation of the medial and lateral perforant pathways in the rat , 1977, The Journal of comparative neurology.

[19]  F. H. Lopes da Silva,et al.  Long-term potentiation and 4-aminopyridine-induced changes in protein and lipid phosphorylation in the hippocampal slice. , 1986, Progress in brain research.

[20]  A. Routtenberg.  Protein kinase C activation leading to protein F1 phosphorylation may regulate synaptic plasticity by presynaptic terminal growth. , 1985, Behavioral and neural biology.

[21]  B. L. McNaughton,et al.  Evidence for two physiologically distinct perforant pathways to the fascia dentata , 1980, Brain Research.

[22]  P. Andersen,et al.  Specific long-lasting potentiation of synaptic transmission in hippocampal slices , 1977, Nature.

[23]  T. Bliss,et al.  Heterosynaptic changes accompany long‐term but not short‐term potentiation of the perforant path in the anaesthetized rat. , 1985, The Journal of physiology.

[24]  J. Winson,et al.  Long-term potentiation in dentate gyrus: induction by asynchronous volleys in separate afferents. , 1986, Science.

[25]  Y. Nishizuka.  Studies and perspectives of protein kinase C. , 1986, Science.

[26]  T. Teyler,et al.  Long-term potentiation. , 1987, Annual review of neuroscience.

[27]  C. Nicholson,et al.  Experimental optimization of current source-density technique for anuran cerebellum. , 1975, Journal of neurophysiology.

[28]  A. Verkleij,et al.  Presynaptic localization of B-50 phosphoprotein: the (ACTH)-sensitive protein kinase substrate involved in rat brain polyphosphoinositide metabolism , 1985, Brain Research.

[29]  A. Routtenberg,et al.  Comparison between the neural acidic proteins B-50 and F1. , 1986, Progress in brain research.

[30]  A. Routtenberg,et al.  A membrane phosphoprotein associated with neural development, axonal regeneration, phospholipid metabolism, and synaptic plasticity , 1987, Trends in Neurosciences.

[31]  L. Kaczmarek.  The role of protein kinase C in the regulation of ion channels and neurotransmitter release , 1987, Trends in Neurosciences.

[32]  S. Snyder,et al.  Mapping second messenger systems in the brain: differential localizations of adenylate cyclase and protein kinase C. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[33]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[34]  D. Linden,et al.  Enhancement of long-term potentiation by cis-unsaturated fatty acid: relation to protein kinase C and phospholipase A2 , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  D. Lovinger,et al.  Selective increase in phosphorylation of a 47-kDa protein (F1) directly related to long-term potentiation. , 1985, Behavioral and neural biology.

[36]  A. Routtenberg,et al.  Direct activation of purified protein kinase C by unsaturated fatty acids (oleate and arachidonate) in the absence of phospholipids and Ca2+ , 1985, FEBS letters.

[37]  G. Collingridge.  Long term potentiation in the hippocampus: mechanisms of initiation and modulation by neurotransmitters , 1985 .

[38]  D. Lovinger,et al.  Phorbol ester promotes growth of synaptic plasticity , 1986, Brain Research.

[39]  R. Racine,et al.  Long-term potentiation phenomena in the rat limbic forebrain , 1983, Brain Research.