Stem-cell-associated structural and functional plasticity in the aging hippocampus.

Aging frequently leads to a functional decline across multiple cognitive domains, often resulting in a severe reduction in life quality and also causing substantial care-related costs. Understanding age-associated structural and functional changes of neural circuitries within the brain is required to improve successful aging. In this review, the authors focus on age-dependent alterations of the hippocampus and the decline of hippocampal function, which are critically involved in processes underlying certain forms of learning and memory. Despite the dramatic reductions in hippocampus-dependent function that accompany advancing age, there is also striking evidence that even the aged brain retains a high level of plasticity. Thus, one promising avenue to reach the goal of successful aging might be to boost and recruit this plasticity, which is the interplay between neural structure, function, and experience, to prevent age-related cognitive decline and age-associated comorbidities. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relative concentrations and seizure-induced changes in mRNAs encoding three AMPA receptor subunits in hippocampus and cortex

In situ hybridization was used to determine 1) the relative concentrations of mRNAs encoding different subunits of the alpha-amino 3-hydroxy-5-methyl-4- isoxazolepropionate receptor family in select regions of rat forebrain and 2) whether limbic seizures alter the balances of the subunit mRNAs. GluR1 and GluR2 mRNA levels were about equal and were much greater than GluR3 mRNA levels in the principal neurons of each hippocampal subdivision. Probable interneurons in hippocampal molecular layers had much higher levels of GluR1 mRNA than of either GluR2 or GluR3 mRNA. Pyramidal cell layers in neo- and paleocortex had a balance of mRNAs that was significantly different from the balance in hippocampus: GluR1 mRNA and GluR3 mRNA levels were about equal and were substantially lower than those of GluR2 mRNA. Lesion-induced limbic seizures caused transient changes in mRNA levels that were differentiated with regard to subunit and brain region. All three mRNAs were decreased in the pyramidal layers of cortex, and changes in hippocampal pyramidal cells were smaller. Seizure-induced changes in granule cells of the dentate gyrus differed from all other regions examined: GluR1 mRNA was reduced to a greater degree than GluR2 mRNA, whereas GluR3 mRNA content was markedly increased. These data strongly suggest that the subunit composition of alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionate receptors differs significantly between areas of the cortical telencephalon. Furthermore, the data indicate that aberrant patterns of physiological activity differentially influence the expression of subunit mRNAs in a region-specific and/or cell-type-specific manner.     

Eukaryotic mRNAs encoding abundant and scarce proteins are statistically dissimilar in many structural features

The ability of H2O2 and tributyltin (TBT) to trigger pro-caspase activation via export of cytochrome c from mitochondria to the cytoplasm was investigated. Treatment of Jurkat T lymphocytes with H2O2 resulted in the appearance of cytochrome c in the cytosol within 2 h. This was at least 1 h before caspase activation was observed. TBT caused cytochrome c release already after 5 min, followed by caspase activation within 1 h. Measurement of mitochondrial membrane potential (delta psi(m)) showed that both H2O2 and TBT dissipated delta psi(m), but with different time courses. TBT caused a concomitant loss of delta psi(m) and release of cytochrome c, whereas cytochrome c release and caspase activation preceded any apparent delta psi(m) loss in H2O2-treated cells. Thus, our results suggest that different mechanisms are involved in triggering cytochrome c release with these apoptosis-inducing agents.     

Expression of mRNAs encoding dopamine receptors in striatal regions is differentially regulated by midbrain and hippocampal neurons

The glutamate analogue kainic acid was injected into the hippocampus of intact or 6-hydroxydopamine deafferented rats to investigate the influence of hippocampal neurons on the expression of dopamine D1 and D2 receptor mRNAs in subregions of the striatal complex and possible modulation by dopaminergic neurons. Quantitative in situ hybridization using 35S-labeled oligonucleotide probes specific for dopamine D1 and D2 receptor mRNAs, respectively, were used. It was found that an injection of kainic acid into the hippocampal formation had alone no significant effect on dopamine D1 or D2 receptor mRNA levels in any of the analyzed striatal subregions in animals analyzed 4 h after the injections. Kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion produced an increase in D1 receptor mRNA levels in the ipsilateral medial caudate-putamen, and a bilateral increase in core and shell of nucleus accumbens (ventral striatal limbic regions). A unilateral 6-hydroxydopamine lesion alone caused an increase in D2 receptor mRNA in the lateral caudate-putamen (dorsal striatal motor region) ipsilateral to the lesion and an increase in D1 receptor mRNA in the accumbens core ipsilateral to the lesion. However, in dopamine-lesioned animals, dopamine D1 receptor mRNA levels were increased bilaterally in nucleus accumbens core and shell and in the ipsilateral medial caudate-putamen following kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion. These results indicate a differential regulation of the expression of dopamine D1 and D2 receptor mRNAs by midbrain and hippocampal neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Associative synaptic plasticity in hippocampus and visual cortex: cellular mechanisms and functional implications

Synchronous pre- and postsynaptic neuronal activity results in long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus and the neocortex. Induction of this form of potentiation requires calcium influx mediated by NMDA receptors. Experimental evidence is reviewed for induction of long-term depression (LTD) of synaptic transmission in the hippocampus in vitro and neocortical neurons in vivo, when the discharge of the postsynaptic neuron is temporally decorrelated from the presynaptic stimulation. Homosynaptic LTD induced by low frequency tetani in the hippocampus in vitro requires NMDA receptor activation and a moderate calcium influx. The role of postsynaptic calcium as a key parameter in the encoding of temporal contiguity of neural activity and its possible implications in the formation of engrams during specific learning tasks are discussed.     

Developmentally regulated changes in the glycoproteins of the equine embryonic capsule

The embryonic capsule, which covers the equine blastocyst after it loses its zona pellucida, is composed of mucin-like glycoproteins. In the present study, we investigated both macroscopic and molecular changes in the capsule during development. The weight of the capsule increased from day 11-12 of pregnancy and reached a maximum at about day 18, coinciding with the time during which the conceptus migrates extensively throughout the uterus. The sialic acid content of the capsule declined markedly from about day 16, the time of conceptus 'fixation' in the uterus, which suggests a unique developmentally regulated mechanism for the control of embryo mobility. These results lead us to propose that the capsule may have an anti-adhesion function in the developing conceptus, and that this effect could be regulated by the sugar side chains of the capsular glycoproteins. The glycosylation characteristics of the blastocyst coverings also underwent changes at about day 9 of pregnancy, which may be related to loss of the zona pellucida. An anti-capsule monoclonal antibody was raised and shown to recognize a tissue-specific antigen present only on the capsule and trophoblast. This antigen was present on the trophoblastic cells soon after the blastocyst is formed, reached a maximum concentration at about day 18, and was absent after day 22, coinciding with the disappearance of the capsule. Immunohistochemical studies indicate that the mucin-like capsular glycoproteins are secreted, at least in major part, by the trophoblast.(ABSTRACT TRUNCATED AT 250 WORDS)     

Developmentally regulated changes in the cell surface architecture of Leishmania parasites

The cell surface of Leishmania parasites is coated by a highly unusual glycocalyx which varies markedly during the parasite life cycle. The predominant molecule on the extracellular promastigote (sandfly) stage is a complex lipophosphoglycan (LPG), which together with a number of GPI-anchored proteins and a family of low molecular weight glycoinositolphospholipids (GIPLs), forms a morphologically distinct protective coat over the plasma membrane. The structure of the LPG has been shown to vary in different species and during promastigote development in the sandfly. This polymorphism is thought to be important in allowing Leishmania parasites to colonize a range of insect hosts, and in facilitating the regulated migration of promastigotes along the sandfly alimentary canal. Stage-specific changes in LPG are also involved in preadapting promastigotes to life in the mammalian host. This complex glycocalyx coat is absent from the amastigote stage that proliferates in the phagolysosomes of mammalian macrophages, as the expression of both the LPG and GPI-anchored proteins is massively down-regulated. Instead, the plasma membrane of amastigotes is coated by a densely packed layer of parasite-derived GIPLs and host-derived glycosphingolipids. We propose that the down-regulation of the promastigote macromolecules and the acquisition of host glycolipids by amastigotes represents an important strategy to avoid detection by specific and non-specific components of the immune system.     

Cloning and functional expression of alternative spliced variants of the rho1 gamma-aminobutyrate receptor

The rho1 gamma-aminobutyrate receptor (GABArho1) is expressed predominantly in the retina and forms homomeric GABA-gated Cl- channels that are clearly different from the multisubunit GABAA receptors. In contrast to these, GABArho1 receptors desensitize very little and are not blocked by bicuculline. In addition to GABArho1, two new variants were identified in human retina cDNA libraries. Cloning and sequence analysis showed that both variants contain large deletions in the putative extracellular domain of the receptor. These deletions extend from a common 5' site to different 3' sites. The cDNA with the largest deletion, named GABArho1Delta450, contains a complete ORF identical to that of GABArho1 but missing 450 nt. This cDNA encodes a protein of 323 aa, identical to the GABArho1, but has a deletion of 150 aa in the amino-terminal extracellular domain. GABArho1Delta450 mRNA injected into Xenopus oocytes did not produce functional GABA receptors. The second GABArho1 variant (GABArho1Delta51) contains a 51-nt deletion. In Xenopus oocytes, GABArho1Delta51 led to the expression of GABA receptors that had the essential GABArho1 characteristics of low desensitization and bicuculline resistance. Therefore, alternative splicing increases the coding potential of this gene family expressed in the human retina, but the functional diversity created by the alternative spliced forms is still not understood.     

Autoantigen Ku in the brain. Developmentally regulated expression and subcellular localization

A double-stranded DNA end-binding factor with high levels of expression in brain and testis of adult mice was identified as the Ku protein, earlier described as an autoantigen in connective tissue diseases and found to be essential for recombination of the immunoglobulin genes and DNA repair. High Ku levels were found in the cerebellum and pituitary gland, lower levels in the hippocampus, hypothalamus and white matter structures. Ku levels were much higher in embryonic rat brain than in the adult brain, suggesting a role of the Ku protein in brain development. In embryonic rat brain, Ku was associated with cell nuclei, but was predominantly located in the cytosol in the adult rat cerebellum and hippocampus. The abundant expression of Ku in the brain suggests the involvement of Ku autoantibodies in the pathogenesis of neuropsychiatric complications in connective tissue diseases.     

Ontogenic expression of natriuretic peptide mRNAs in postnatal rat brain: implications for development?

The central natriuretic peptide system is composed of at least three structurally homologous and uniquely distributed peptides and receptors which are thought to be involved in the central regulation of cardiovascular and autonomic function and more recently been shown to affect cellular growth and proliferation, processes pertinent to mammalian development. As such, following our initial mapping of preproatrial natriuretic peptide (ppANP) mRNA in adult brain [M.C. Ryan, A.L. Gundlach, Anatomical localization of preproatrial natriuretic peptide mRNA in the rat brain by in situ hybridization histochemistry: in olfactory regions, J. Comp. Neurol., 356 (1995) 168-182], it was of interest to determine the ontogenic expression of natriuretic peptide mRNAs in the developing rat brain. Using in situ hybridization histochemistry of specific [35S]- or [33P]-labeled oligonucleotides, ppANP and preproC-type natriuretic peptide (ppCNP) mRNAs were detected in the developing rat brain from postnatal day 4 to day 60 (adult). PpANP mRNA was observed in many hindbrain, but only some forebrain, regions at postnatal day 4. Regional differences in the temporal expression of ppANP mRNA were apparent with ppANP mRNA detected in the medial preoptic area, mammillary nuclei and medial habenular nucleus at postnatal day 4 and in other areas including the arcuate and dorsomedial hypothalamic nuclei and in olfactory and limbic regions at postnatal day 10. A number of regions also exhibited transient expression of ppANP mRNA such as the bed nucleus of the stria terminalis and the medial cerebellar nucleus. In contrast, ppCNP mRNA was detected at relatively high levels in several regions on postnatal day 4 including olfactory nuclei, the hippocampus and particularly the pontine nucleus. The level of expression appeared to increase markedly in most regions including forebrain olfactory and hippocampal areas and in brainstem regions including the pontine nucleus, the parvocellular and lateral reticular and spinal trigeminal nuclei by postnatal days 10 and 13, but decreased from this peak to equivalent to adult levels by postnatal day 28. The differential and transient expression of the natriuretic peptides during postnatal development, together with previous reports of the ontogenic regulation of natriuretic peptide receptor expression and binding patterns, further suggests their involvement in developmental processes in the rat CNS and provides information relevant to the likely functional development of natriuretic peptide-utilizing pathways.     

Expression of fibronectin splicing variants in organ transplantation: a differential pattern between rat cardiac allografts and isografts

Allograft rejection is associated with infiltration of inflammatory cells and deposition of extracellular matrix proteins. The extent to which diversity in the extracellular matrix regulates inflammatory cell function in transplants remains unclear. One group of extracellular matrix proteins, termed fibronectins (FNs), exhibits inherent diversity as a consequence of alternative splicing in three segments: EIIIA, EIIIB, or V. Although the EIIIA segment has documented functions in mesenchymal cell differentiation, neither this segment nor the EIIIB segment have been tested for effects specific to leukocyte functions. By contrast, the V region can include the CS-1 segment to which leukocytes may adhere through alpha 4 beta 1 integrins. In this study, we demonstrate that EIIIA+, EIIIB+, and V+ FN variants are synthesized, primarily by macrophages in distinct temporal and spatial patterns in two rat cardiac transplant models: either with antigenic challenge, allografts, or without challenge, isografts. The ratio of EIIIA inclusion into FN increases by day 1 in allografts and isografts and remains high until allografts are rejected (approximately 7 days) but falls to normal levels in tolerated isografts (day 6). EIIIB+ FN ratios in allografts peak later than do EIIIA+ FNs (day 4). EIIIB+ FN ratios remain relatively low in isografts. Interestingly, EIIIA+ and EIIIB+ FNs are deposited prominently in the myocardium of rejecting allografts in close association with infiltrating leukocytes, and FN expression and deposition are prominent at sites of infarction. By contrast, these FNs are largely restricted to the epicardium and to a lesser degree in the immediately adjacent myocardium in isografts. CS-1+ FNs increase in allografts and isografts at 3 hours after transplantation but are particularly prominent in allografts 1 to 3 days before rejection. Our data suggest that FN splicing variants have a differential role in the effector functions of leukocytes in allografts and isografts and provide a foundation for testing their function on leukocytes and a rationale for FN-based therapeutics to modulate allograft rejection in transplant recipients.     

Developmentally regulated expression of persyn, a member of the synuclein family, in skin

Synucleins constitute a group of unique, evolutionarily conserved proteins that are expressed predominantly in neurons of the central and peripheral nervous system. Although the normal cellular functions of synucleins are not clear, these proteins have been implicated in various neurodegenerative conditions in humans. We found that persyn, a recently characterized member of the synuclein family, is expressed not only in the nervous system but also in the stratum granulosum of the epidermis of neonatal and adult mice. This finding together with our recent observations that persyn influences neurofilament network integrity in sensory neurons raises the possibility that persyn in skin could be involved in modulation of the keratin network.