Historical review of research on protein kinase C in learning and memory

1. In 1977, the discovery of a new type of kinase was reported, which turned out to be a receptor for phorbol esters. Thereafter, several mechanisms regulating PKC activity and various PKC subtypes have been discovered. 2. A role for PKC in synaptic plasticity and information storage has been postulated in the mid-1980s. An important role for PKC has since been suggested in several learning and memory models, in which persistent changes in the activation of PKC outlasting the initial stimulating event are thought to be crucial. 3. A vast number of experiments have further substantiated a role of PKC in learning and memory using molecular genetic, behavioral, pharmacological, electrophysiological or immunocytochemical approaches in the late 1980s and the 1990s. PKC research of the past decade or so of has shown some exciting aspects of the putative role of PKC in synaptic plasticity and information storage. 4. The authors have provided highlights (Table 1) on research on PKC

Noradrenergic and cholinergic reinnervation of islet grafts in diabetic rats

Grafted islets become denervated due to the islet transplantation procedure. The aim of the present study was 1) to examine whether islet grafts in the liver, the spleen, and under the kidney capsule in rats become reinnervated following the transplantation and experimental procedures used in our laboratory, 2) whether there is any difference in reinnervation at these different sites, and 3) how these results relate to previous physiological experiments. Isogeneic isolated islets were transplanted into diabetic Albino Oxford rats, resulting in normoglycaemia. After at least 5 wk, graft-receiving organs were removed and several antibodies were employed to detect insulin, neuron-specific proteins, and cholinergic and noradrenergic nerve fibers. Islets in all three receiving organs contained viable insulin-positive B-cells. Neuron-specific enolase (NSE) as well as the growth-associated protein B-50 was observed at all sites. The cholinergic marker choline acetyltransferase (ChAT) was localized in islets grafts at all sites, but with the lowest density in the spleen. Staining for the noradrenergic markers tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) was observed in islet grafts at all sites with the lowest density in grafts under the kidney capsule. All these neurochemical substances were most frequently observed in fibers associated with blood vessels, which may be the route along which nerves grow into the graft. It can be concluded that 1) islet grafts in the liver, in the spleen and under the kidney capsule become reinnervated; 2) the innervation pattern of the islet grafts differs only slightly from that in the control pancreatic islets; and 3) in combination with our previously physiological data, we can conclude that these nerve fibers are, at least partly, functionally active

Divergence between Human Populations Estimated from Linkage Disequilibrium

Observed linkage disequilibrium (LD) between genetic markers in different populations descended independently from a common ancestral population can be used to estimate their absolute time of divergence, because the correlation of LD between populations will be reduced each generation by an amount that, approximately, depends only on the recombination rate between markers. Although drift leads to divergence in allele frequencies, it has less effect on divergence in LD values. We derived the relationship between LD and time of divergence and verified it with coalescent simulations. We then used HapMap Phase II data to estimate time of divergence between human populations. Summed over large numbers of pairs of loci, we find a positive correlation of LD between African and non-African populations at levels of up to ∼0.3 cM. We estimate that the observed correlation of LD is consistent with an effective separation time of approximately 1,000 generations or ∼25,000 years before present. The most likely explanation for such relatively low separation times is the existence of substantial levels of migration between populations after the initial separation. Theory and results from coalescent simulations confirm that low levels of migration can lead to a downward bias in the estimate of separation time

REVERSED ALTERATIONS OF HIPPOCAMPAL PARVALBUMIN AND PROTEIN-KINASE C-GAMMA IMMUNOREACTIVITY AFTER STROKE IN SPONTANEOUSLY HYPERTENSIVE STROKE-PRONE RATS

Background and Purpose: Aging spontaneously hypertensive stroke-prone rats (SHR-SP) were previously shown to develop neocortical strokes. Because the hippocampal CA1 is selectively vulnerable to abnormal brain perfusion, the neuropathological effects of spontaneous strokes were investigated on specific neurochemical alterations in two major cell types of the hippocampal CA1 in SHR-SP. Methods: The immunoreactivity for the gamma-isoform of protein kinase C (in pyramidal cells) and parvalbumin (in interneurons) was determined in the hippocampal CA1 by applying monoclonal antibodies. Because chronic treatment with the calcium antagonist nimodipine prevents the development of strokes in SHR-SP, we compared SHR-SP (stroke) with age-matched nimodipine-treated rats (nonstroke). Results: After stroke in control animals, we observed a strikingly enhanced immunoreactivity for protein kinase C-gamma in CA1 pyramidal cells compared with nimodipine-treated rats, which can be interpreted as the result of an increased activation of these cells. The pathological increase of protein kinase C-gamma immunoreactivity was accompanied by a reduced parvalbuminergic innervation of these pyramidal cells in symptomatic SHR-SP. Conclusions: Because parvalbumin is present in a subset of GABAergic inhibitory interneurons, these data suggest that increased activity of CA1 pyramidal cells after spontaneous stroke may partially be related to a decreased inhibitory input on these cells

COLOCALIZATION OF MUSCARINIC ACETYLCHOLINE-RECEPTORS AND PROTEIN KINASE-C-GAMMA IN RAT PARIETAL CORTEX

The present investigation analyzes the cellular distribution of muscarinic acetylcholine receptors (mAChRs) and the gamma isoform of protein kinase C (PKC) in the rat parietal cortex employing the monoclonal antibodies M35 and 36G9, respectively. Muscarinic cholinoceptive neurons were most present in layers 2, 3 and 5, whereas most PKCgamma-positive cells were found in layers 2, 5 and 6. Under normal, non-stimulated conditions, approximately 58% of all muscarinic cholinoceptive neurons were immunoreactive for PKCgamma. Conversely, nearly all PKCgamma-positive neurons were M35-immunoreactive. Although both pyramidal and nonpyramidal neurons express the two types of protein, the pyramidal cell type represents the vast majority. Of all cortical neurons, the large (15-25 mu m in diameter) muscarinic cholinoceptive pyramidal neurons in layer 5 express the gamma isoform of PKC most abundantly and most frequently. Approximately 96% of these cells are immunoreactive for PKCgamma. Stimulation of mAChRs by the cholinergic agonist carbachol resulted in a pronounced increase in the intensity of 36G9 immunoreactivity, which may suggest that the mAChRs are functionally linked to the colocalized PKCgamma. No change was found in the number of 36G9-immunoreactive neurons. In contrast, the number of immunocytochemically detectable muscarinic cholinoceptive neurons increased by approximately 38% after carbachol stimulation. The high degree of codistribution in cortical neurone of both transduction proteins suggests a considerable cholinergic impact upon the regulation of PKCgamma, a candidate key enzyme in cortical learning and memory mechanisms