Role of protein kinase C in modulation of excitability of CA1 pyramidal neurons in the rat.
Biochemical and in situ hybridization studies demonstrated that the levels of protein kinase C variants were significantly increased in the hippocampus of the experimental models of epilepsy in rats. In addition it has been demonstrated that protein kinase C plays an important role in modulating synaptic transmission in the hippocampus. We examined the effects of activating of protein kinase C on the excitability of CA1 pyramidal neurons and synaptic transmission, using whole-cell current-clamp and extracellular field potential recording techniques. Indolactam V (1 microM) a novel protein kinase C activator, increased the excitability of CA1 neurons acting at both pre- and post-synaptic sites. Indolactam V, acting postsynaptically, significantly reduced the threshold for initiation of action potential from -42+/-3.8 mV to -51+/-3.1 mV and selectively inhibited the slow afterhyperpolarizing potential. Indolactam V also altered the neuronal firing properties in response to prolonged depolarizing pulse by eliminating the spike frequency accommodation. Our data indicate that indolactam V potentiated both amplitudes of Shaffer-collateral stimulation evoked excitatory postsynaptic currents and disynaptically evoked inhibitory evoked postsynaptic currents. However, the potentiation of inhibitory evoked postsynaptic currents amplitudes was not observed after blockade of NMDA and AMPA/kainate currents suggesting it was due to excitatory activity driving inhibitory neurons. The results indicate that the potentiation of pharmacologically isolated excitatory postsynaptic currents (215% of control) and amplitudes of population spikes (290% of control) was due to action of indolactam V presynaptically since the agonist reduced the paired-pulse ratio and the potentiating effect was not blocked by dialyzing the postsynaptic neuron through the recording electrode with a specific protein kinase C inactivator calphostin C. These findings suggest that protein kinase C increases the amplitude of epileptiform activity by causing potentiation of excitatory synaptic transmission, increasing the excitability of postsynaptic neurons and reducing negative feed back provided by slow afterhyperpolarizing potential.
Neuroscience Research Group, School of Biological Sciences, University of Southampton, Bassett Crescent East, UK.
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Grabauskas
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Chapman
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Wheal
D000818:Animals; D000831:Animals, Newborn; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007769:Lactams / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010852:Picrotoxin / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D000697:Central Nervous System Stimulants; D007211:Indoles; D007769:Lactams; D010852:Picrotoxin; D011493:Protein Kinase C; C043969:indolactam V