Evolution of the "classical" cadherin family of cell adhesion molecules in vertebrates

The cadherins are major mediators of calcium-dependent cell-cell adhesion and are also involved in cell signaling pathways during development. The classical cadherins, which are the definitive group of the cadherin superfamily, are transmembrane proteins that consist of an extracellular domain of five cadherin repeats, including an HAV tripeptide conserved in one binding surface within the first domain, and a highly conserved cytoplasmic domain that interacts with the actin cytoskeleton via the catenin proteins. These cadherins play major roles in vertebrate morphogenesis; they are expressed widely throughout development, antibodies to specific cadherins perturb a variety of developmental processes, and many gene knockouts are lethal at early stages of development. Phylogenetic analysis of the "classical" cadherins shows that in the vertebrates there are four paralog families. The rate of evolutionary change is radically different between the different paralogs, indicating that there are significantly different selection pressures on the functions of the various cadherins, both between the different paralogs in a single organism lineage and between different organism lineages within a single paralog family. There is also evidence for gene conversion between the E-cadherin and P-cadherin paralogs in Gallus gallus and possibly Xenopus laevis, but not between the same paralogs in the mammalian lineages. A scheme for the origin of the paralogs within the vertebrate lineage based on these analyses indicates that the presence of the four paralog families is a characteristic of vertebrates and that variation of cadherin structure and function is a significant factor in morphological evolution of vertebrates.     

Involvement of dendritic adhesion molecule telencephalin in hippocampal long-term potentiation

Telencephalin (TLCN) is a cell adhesion molecule belonging to the immunoglobulin superfamily whose expression is restricted to neurons within the most highly developed brain segment, telencephalon. Immunoelectronmicroscopic study revealed that in the hippocampal CA1 region, TLCN was localized at the surface membrane of postsynaptic spines of pyramidal cell dendrites but not at that of axonal terminals. Blocking of TLCN function using anti-TLCN antibody or recombinant soluble TLCN protein caused a striking suppression of the long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses. The suppression was observed even when the blocking was initiated immediately after the tetanic stimuli. These observations suggest a role for TLCN-mediated cell-cell interactions as a key step in the development of LTP.     

A role for c-Raf kinase and Ha-Ras in cytokine-mediated induction of cell adhesion molecules

Cytokines such as tumor necrosis factor (TNFalpha) play fundamental roles in the pathophysiology of inflammation and immunity-related diseases. Despite rapid advances in our understanding of cytokine biology in recent years, definitive knowledge of the cytokine cell signaling pathways remains elusive due to the enormous complexity of these pathways and the lack of specific biological tools and reagents. Using highly specific antisense oligonucleotides that target the mRNA encoding c-Raf kinase and Ha-Ras, we show here that inhibition of c-raf and Ha-ras expression blocks the up-regulation of E-selectin and vascular adhesion molecule-1 induced by TNFalpha in endothelial cells. Induction of intercellular adhesion molecule-1 was also reduced, although to a much lesser extent, by treatment with antisense oligonucleotides. We also show that inhibition of c-raf kinase expression decreased extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK) kinase stimulation by TNFalpha. Furthermore, antisense inhibition of JNK2 also blocked TNFalpha-mediated induction of E-selectin, whereas PD98059 (mitogen-activated protein kinase kinase 1 and 2 inhibitor) had no effect on this process. These results indicate that TNFalpha induction of E-selectin and vascular adhesion molecule-1 in endothelial cells occurs through signaling pathways that are, at least in part, dependent on c-Raf kinase, Ha-Ras, and JNK2.     

Modified hippocampal long-term potentiation in PKC gamma-mutant mice

Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the gamma subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKC gamma is not part of the molecular machinery that produces LTP but is a key regulatory component.     

Cognitive enhancers and hippocampal long-term potentiation in vitro

We review our works on the pharmacological modulation of long-term potentiation (LTP) at guinea pig hippocampal mossy fiber-CA3 synapses in vitro. The magnitude of tetanus-induced LTP at the mossy fiber synapse was augmented by perfusion of slices with several cognitive enhancers, such as bifemelane (1 microM). The mossy fiber LTP was enhanced by somatostatin (0.32 microM) and inhibited in somatostatin-depleted slices from cysteamine-treated guinea pigs. An involvement of the 5-HT3 receptor also showed that granisetron (0.1 microM) enhanced the mossy fiber LTP. The above-mentioned enhancements by perfused agents were commonly reversed, at least in part, by muscarinic antagonists. However, the magnitude of mossy fiber LTP was bidirectionally modulated by muscarinic stimulations of slices with physostigmine or carbachol at different concentrations. The enhancing effects of high-concentration carbachol was antagonized by pirenzepine, and in contrast, the inhibition by low-concentration carbachol was antagonized in the presence of AF-DX116. When guinea pigs were preinjected with the cholinotoxin AF64A, the magnitude of LTP was decreased in the slices prepared from AF64A-treated animals. These results suggest that endogenous acetylcholine dominantly plays facilitatory roles through muscarinic M1 receptors in the induction of mossy fiber LTP. The pharmacological characterization of mossy fiber LTP may be of help to the evaluation of cognitive enhancers at a neuronal circuit level.     

Two forms of hippocampal long-term depression, the counterpart of long-term potentiation

In the hippocampus there are two distinct forms of long-term depression (LTD) of excitatory synaptic transmission. In the CA1 region, prolonged low-frequency stimulation induces LTD by activating postsynaptic NMDA receptors, which causes a moderate rise in Ca2+ concentrations. In mossy fiber synapses of the CA3 region, similar low-frequency stimulation also gives rise to LTD. However, this form of LTD (mossy fiber LTD) does not require activation of NMDA receptors, but is mediated by activation of presynaptic metabotropic glutamate receptors. Induction of mossy fiber LTD is not dependent on postsynaptic depolarization or activation of postsynaptic ionotropic glutamate receptors, thus it is likely to be mediated by purely presynaptic mechanisms. This conclusion is confirmed by the analysis of mutant mice lacking presynaptic mGluR2, in which mossy fiber LTD is almost absent. Since long-term potentiation at mossy fiber synapses is also induced presynaptically, the synaptic efficacy may be regulated through common mechanisms bidirectionally, which may contribute to neural information processing in the hippocampus.     

Amygdala beta-noradrenergic influence on hippocampal long-term potentiation in vivo

We have previously shown that hippocampal long-term potentiation (LTP), one form of synaptic plasticity that may underlie learning and memory, is attenuated by blocking neuron activity of the basolateral amygdala (BLA). In the present study we investigated the amygdala noradrenergic or cholinergic contribution to hippocampal LTP formation. When propranolol, a beta-adrenoceptor antagonist, was injected into the BLA 10 min before tetanus, the formation of LTP in the perforant path-dentate granule cell synapses was significantly impaired. Scopolamine, a muscarinic cholinergic receptor antagonist, did not affect the formation of LTP. These results suggest that amygdala beta-noradrenergic activity plays a critical role in modulation of hippocampal LTP.     

Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation

A novel property of hippocampal LTP, 'variable persistence', has recently been described that is, we argue, relevant to the role of LTP in information storage. Specifically, new results indicate that a particular pattern of synaptic activation can give rise, either to a relatively short-lasting LTP, or to a longer-lasting LTP as a function of the history of activation of the neuron. This has led to the idea that the induction of LTP is associated with the setting of a'synaptic tag' at activated synapses, whose role is to sequester plasticity-related proteins that then serve to stabilize temporary synaptic changes and so extend their persistence. In this article, we outline the synaptic tag hypothesis, compare predictions it makes with those of other theories about the persistence of LTP, and speculate about the cellular identity of the tag. In addition, we outline the requirement for aminergic activation to induce late LTP and consider the functional implications of the synaptic tag hypothesis with respect to long-term memory.     

Protected-site phosphorylation of protein kinase C in hippocampal long-term potentiation

One important aspect of synaptic plasticity is that transient stimulation of neuronal cell surface receptors can lead to long-lasting biochemical and physiological effects in neurons. In long-term potentiation (LTP), generation of autonomously active protein kinase C (PKC) is one biochemical effect persisting beyond the NMDA receptor activation that triggers plasticity. We previously observed that the expression of early LTP is associated with a phosphatase-reversible alteration in PKC immunoreactivity, suggesting that autophosphorylation of PKC might be elevated in LTP. In the present studies we tested the hypothesis that PKC phosphorylation is persistently increased in the early maintenance of LTP. We generated an antiserum that selectively recognizes the alpha and betaII isoforms of PKC autophosphorylated in the C-terminal domain. Using western blotting with this antiserum we observed an NMDA receptor-mediated increase in phosphorylation of PKC 1 h after LTP was induced. How is the increased phosphorylation maintained in the cell in the face of ongoing phosphatase activity? We observed that dephosphorylation of PKC in vitro requires the presence of cofactors normally serving to activate PKC, i.e., Ca2+, phosphatidylserine, and diacylglycerol. Based on these observations and computer modeling of the three-dimensional structure of the PKC catalytic core, we propose a "protected site" model of PKC autophosphorylation, whereby the conformation of PKC regulates accessibility of the phosphates to phosphatase. Although we have proposed the protected site model based on our studies of PKC phosphorylation in LTP, phosphorylation of protected sites might be a general biochemical mechanism for the generation of stable, long-lasting physiologic changes.     

Early undernutrition impairs hippocampal long-term potentiation in adult rats.

Investigated the effects of early malnutrition on the ability to establish and maintain hippocampal long-term potentiation (LTP), a relatively permanent enhancement of synaptic and cellular responses induced by high-frequency stimulation. Six control male rats and 8 previously undernourished Ss were used in the acute preparation, and 4 controls and 6 previously undernourished Ss in the chronic preparation. Following high-frequency stimulation of hippocampal dentate granule cells, potentiation was difficult to achieve in undernourished Ss. LTP showed a significant decline within 3–6 hrs and was completely absent at 24 hrs. Further trains of stimulation resulted in only small benefits in undernourished Ss. Coupled with previously reported morphological and behavioral deficits, these findings indicate a marked hippocampal dysfunction resulting from early undernutrition and provide a potentially valuable approach for relating nutritionally induced behavioral impairments to brain function. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Src activation in the induction of long-term potentiation in CA1 hippocampal neurons

Long-term potentiation (LTP) is an activity-dependent strengthening of synaptic efficacy that is considered to be a model of learning and memory. Protein tyrosine phosphorylation is necessary to induce LTP. Here, induction of LTP in CA1 pyramidal cells of rats was prevented by blocking the tyrosine kinase Src, and Src activity was increased by stimulation producing LTP. Directly activating Src in the postsynaptic neuron enhanced excitatory synaptic responses, occluding LTP. Src-induced enhancement of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor-mediated synaptic responses required raised intracellular Ca2+ and N-methyl-D-aspartate (NMDA) receptors. Thus, Src activation is necessary and sufficient for inducing LTP and may function by up-regulating NMDA receptors.     

The role of adhesion molecules in atherosclerosis

The progression of atherosclerosis is currently believed to involve the interaction of monocytes with the vascular endothelium. Within the last decade, the cell-surface proteins thought to control these interactions have been investigated. This review seeks to describe the nature of these interactions through what are known as adhesion molecules and their role in atherogenesis. It begins with the stages of atherogenesis from the movement of the monocyte to the endothelium, followed by the migration of smooth muscle cells from the media to the intima, and subsequently to the later stages of fibrofatty plaque formation and potential complications due to thrombosis and/or plaque fissure and embolism. The different structural classifications of the adhesion molecules, such as integrins, cadherins, selectins, and members of the immunoglobulin gene superfamily, are outlined, and interaction of binding domains are highlighted. The vascular endothelium and the basic role of adhesion molecules in dysfunction are considered. Discussion of the role of adhesion molecules in atherogenesis focuses on interactions of the endothelium, monocytes, and leukocytes, as well as the influences of cytokines, oxidized low-density lipoproteins, and genetic determinants. Finally, epidemiological risk factors associated with atherosclerosis such as hypertension and dyslipidemia are considered in light of their effects on adhesion molecule expression.     

A role for cAMP in long-term depression at hippocampal mossy fiber synapses

Mossy fiber synapses on hippocampal CA3 pyramidal cells, in addition to expressing an NMDA receptor-independent form of long-term potentiation (LTP), have recently been shown to express a novel presynaptic form of long-term depression (LTD). We have studied the mechanisms underlying mossy fiber LTD and present evidence that it is triggered, at least in part, by a metabotropic glutamate receptor-mediated decrease in adenylyl cyclase activity, which leads to a decrease in the activity of the cAMP-dependent protein kinase (PKA) and a reversal of the presynaptic processes responsible for mossy fiber LTP. The bidirectional control of synaptic strength at mossy fiber synapses by activity therefore appears to be due to modulation of the cAMP-PKA signaling pathway in mossy fiber boutons.     

Integrins: a role for adhesion molecules in olfactory memory

A gene required for short-term memory in Drosophila, Volado, encodes an alpha integrin and is preferentially expressed in the mushroom bodies of the adult brain. Adhesion molecules of this kind may play a role in olfactory memory by altering the strength of synaptic connections in an experience-dependent manner.     

Putative role of adhesion molecules in metabolic disorders

Diabetes mellitus is associated with an increased risk of premature vascular disease. Vascular research is focusing on a potential role of adhesion molecules in diabetes mellitus, since classical risk factors including hyperlipidemia and hypertension do not completely account for the increased incidence of atherosclerosis in diabetes. After the expression of adhesion molecules on the cell surface, they are shed into plasma. Thus plasma concentrations of circulating adhesion molecules may be representative for endothelial activation, damage or turnover. Recently, evidence has been accumulating that increased plasma levels of adhesion molecules may predict cardiovascular disease, may be pathognomonic for diabetic microangiopathy or may even play a functional pathophysiologic role. The purpose of this article is to briefly summarise the role of (circulating) adhesion molecules in diabetes mellitus.     

An essential role for protein phosphatases in hippocampal long-term depression

The effectiveness of long-term potentiation (LTP) as a mechanism for information storage would be severely limited if processes that decrease synaptic strength did not also exist. In area CA1 of the rat hippocampus, prolonged periods of low-frequency afferent stimulation elicit a long-term depression (LTD) that is specific to the stimulated input. The induction of LTD was blocked by the extracellular application of okadaic acid or calyculin A, two inhibitors of protein phosphatases 1 and 2A. The loading of CA1 cells with microcystin LR, a membrane-impermeable protein phosphatase inhibitor, or calmodulin antagonists also blocked or attenuated LTD. The application of calyculin A after the induction of LTD reversed the synaptic depression, suggesting that phosphatase activity is required for the maintenance of LTD. These findings indicate that the synaptic activation of protein phosphatases plays an important role in the regulation of synaptic transmission.     

Three-dimensional structure of cell adhesion molecules

Recent structural data have provided insights into various forms of specific cell adhesion interactions, including both protein-protein and protein-glycoconjugate recognition events. The major advances have been made in the structural characterization of cadherin-cadherin and integrin-ligand mediated adhesion.     

The role of adhesion molecules in the immunopathogenesis of atherosclerosis

Advances in the studies on the structure and role of adhesive particles make possible putting forward of the hypothesis that they may also play a significant role in the immunopathogenesis of atherosclerosis. It was demonstrated that in the earliest phase of atherosclerosis development, increased adhesion occurred of monocytes to the vascular endothelium, while autopsy examinations showed the presence of monocytes and T-cells within atherosclerotic lesions. The present studies concentrate on the role of individual adhesive particles as determinants of the above phenomena.     

Effects of prenatal protein malnutrition on hippocampal long-term potentiation in freely moving rats

It has been demonstrated that prenatal protein malnutrition significantly affects hippocampal plasticity, as measured by long-term potentiation, throughout development. This paper focuses on the hippocampal dentate granule cell population response to two separate paradigms of tetanization of the medial perforant pathway in prenatally protein-malnourished and normally nourished adult male rats. The 100-pulse paradigm consisted of the application of ten 25-ms-duration bursts of 400 Hz stimulation with an interburst interval of 10 s. The 1000-pulse paradigm consisted of the application of five 500-ms bursts of 400 Hz stimulation with an interburst interval of 5 s. No between-group differences were obtained for input/output response measures prior to tetanization. No between-group, nor between-paradigm, differences were obtained in the degree of population EPSP slope enhancement. However, in response to both paradigms, prenatally malnourished animals showed significantly less enhancement of the population spike amplitude (PSA) measure than normally nourished animals. Normally nourished animals showed a significantly greater level of PSA enhancement in response to the 100-pulse paradigm than the 1000-pulse paradigm. Prenatally malnourished animals showed no significant differences in the degree of PSA enhancement between the two paradigms. Results indicate that short duration bursts (< or = 25 ms) are more effective in inducing maximal PSA enhancement in normally nourished rats than longer duration stimulus bursts. The apparent inability of prenatally malnourished rats to transfer enhanced cellular activation (population EPSP slope enhancement) into enhanced cellular discharge (PSA enhancement) suggests that a preferential enhancement of GABAergic inhibitory modulation of granule cell excitability may result from the prenatal dietary insult. Such potentiation of inhibitory activity would significantly lower the probability of granule cell population discharge, resulting in the significantly lower level of PSA enhancement obtained from these animals.