Do stress and long-term potentiation share the same molecular mechanisms?

Stress is a biological, significant factor shown to influence hippocampal synaptic plasticity and cognitive functions. Although numerous studies have reported that stress produces a suppression in long-term potentiation (LTP; a putative synaptic mechanism underlying learning and memory), little is known about the mechanism by which this occurs. Because the effects of stress on LTP and its converse process, long-term depression (LTD), parallel the changes in synapticity that occur following the establishment of LTP with tetanic stimulation (i.e., occluding LTP and enhancing LTD induction), it has been proposed that stress affects subsequent hippocampal plasticity by sharing the same molecular machinery required to support LTP. This article summarizes recent findings from ours and other laboratories to assess this view and discusses relevant hypotheses in the study of stress-related modifications of synaptic plasticity.     

Impaired hippocampal long-term potentiation and failure of learning in β1,4-N-acetylgalactosaminyltransferase gene transgenic mice

Gangliosides (sialic acid-containing glycosphingolipids) play important roles in many physiological functions, including synaptic plasticity in the hippocampus, which is considered as a cellular mechanism of learning and memory. In the present study, three types of synaptic plasticity, long-term potentiation (LTP), long-term depression (LTD) and reversal of LTP (depotentiation, DP), in the field excitatory post-synaptic potential in CA1 hippocampal neurons and learning behavior were examined in β1,4-N-acetylgalactosaminyltransferase (β1,4 GalNAc-T; GM2/GD2 synthase) gene transgenic (TG) mice, which showed a marked decrease in b-pathway gangliosides (GQ1b, GT1b and GD1b) in the brain and isolated hippocampus compared with wild-type (WT) mice. The magnitude of the LTP induced by tetanus (100 pulses at 100?Hz) in TG mice was significantly smaller than that in control WT mice, whereas there was no difference in the magnitude of the LTD induced by three short trains of low-frequency stimulation (LFS) (200 pulses at 1?Hz) at 20?min intervals between the two groups of mice. The reduction in the LTP produced by delivering three trains of LFS (200 pulses at 1?Hz, 20?min intervals) was significantly greater in the TG mice than in the WT mice. Learning was impaired in the four-pellet taking test (4PTT) in TG mice, with no significant difference in daily activity or activity during the 4PTT between TG and WT mice. These results suggest that the overexpression of β1,4 GalNAc-T resulted in altered synaptic plasticity of LTP and DP in hippocampal CA1 neurons and learning in the 4PTT, and this is attributable to the shift from b-pathway gangliosides to a-pathway gangliosides.     

Motivation and placebos: do different mechanisms occur in different contexts?

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic-pituitary-adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.     

Inhibition of associative long-term depression by activation of β-adrenergic receptors in rat hippocampal CA1 synapses

The aim of this study was to investigate the role of β-adrenergic receptors in modulating associative long-term depression (LTD) at CA1 synapses in rat hippocampal slices. Standard extracellular electrophysiological techniques were employed to record field excitatory post-synaptic potential (fEPSP) activity and to induce associative LTD. Two independent Schaffer collateral pathways were elicited in hippocampal CA1 areas. In one (weak) pathway, the stimulating intensity was adjusted to elicit small fEPSP activity (20–30% of the maximum response). In contrast, 80–90% of the maximum response was evoked in the other (strong) pathway. Associative LTD of weak pathway could be induced by paired stimulation of weak and the strong pathways, repeated 100 times at 0.167 Hz. The associative LTD of weak pathway was NMDA receptor- and phophatase 2B dependent, because bath application of 50 μM D, L-AP5 or 10 μM cypermethrin blocked its induction. Bath application of 1 μM isoproterenol inhibited associative LTD, and this effect was blocked by timolol, suggesting the involvement of β-adrenergic receptors. The inhibitory effect of β-adrenergic receptors on LTD induction was blocked in slices pretreated with inhibitors of protein kinase A and mitogen-activated protein kinase, suggesting that these signal cascades are downstream effectors following activation of β-adrenergic receptors. Nevertheless, bath application of timolol or cypermethrin alone did not have significant effect on associative LTD induction, suggesting neither endogenous function of β-adrenergic receptor nor endogenous PKA activity does have a role in associative LTD induction.     

What is the function of receptor and membrane endocytosis at the postsynaptic neuron?

This paper explores the implications of certain new developments in cell biology upon neuroscience. Until recently it was thought that neurotransmitters and neuromodulators had only one function, which was to stimulate their specific receptors at the cell surface. From here on, all activity was supposed to be effected by postsynaptic cascades. The discovery that membrane components, particularly G-protein-linked receptors, are not static but are subject to a massive and complex process of continual endocytosis, processing in the endosome system and recycling back to the external membrane, raises the question of its functional significance. In addition, it has been found that many neuromodulators such as polypeptides have their main locus of action inside the postsynaptic neuron. This review covers the role of the endocytic mechanism on receptor desensitization and resensitization, synaptic reorganization and plasticity synaptic scaling and the possible repair of oxidative damage. The possible involvement of this system in Alzheimer's disease is discussed.     

Epigenetic setting for long-term expression of estrogen receptor α and androgen receptor in cells

Epigenetic regulation of the nuclear estrogen and androgen receptors, ER and AR, constitutes the molecular basis for the long-lasting effects of sex steroids on gene expression in cells. The effects prevail at hundreds of gene loci in the proximity of estrogen- and androgen-responsive elements and many more such loci through intra- and even inter-chromosomal level regulation. Such a memory system should be active in a flexible manner during the early development of vertebrates, and later replaced to establish more stable marks on genomic DNA. In mammals, DNA methylation is utilized as a very stable mark for silencing of the ERα and AR isoform expression during cancer cell and normal brain development. The factors affecting the DNA methylation of the ERα and AR genes in cells include estrogen and androgen. Since testosterone induces brain masculinization through its aromatization to estradiol in a narrow time window of the perinatal stage in rodents, the autoregulation of estrogen receptors, especially the predominant form of ERα, at the level of DNA methylation to set up the “cell memory” affecting the sexually differentiated status of brain function has been attracting increasing attention. The alternative usage of the androgen-AR system for brain masculinization and estrogenic regulation of AR expression in some species imply that the DNA methylation pattern of the AR gene can be established by closely related but different systems for sex steroid-induced phenomena, including brain masculinization.     

What are the molecular mechanisms of neural tube defects?

Neural tube defects (NTDs) are some of the most common human malformations. The vast majority of NTDs can be prevented by the administration of folic acid; however, to date there has been no effective treatment of folic acid-resistant NTDs. A recent paper¹ has confirmed an earlier report² that the administration of inositol to the curly tail mutant mouse, which is a model of folate-resistant NTDs, can cure such defects. The molecular pathway by which this is achieved is thought to occur by the up-regulation of the retinoic acid receptor β in the underlying hindgut endoderm, correcting a proliferation defect. However, alternative explanations also may account for NTDs. BioEssays 20:6–8, 1998. © 1998 John Wiley & Sons, Inc.     

Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats

β-Amyloid (Aβ) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aβ in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16 kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aβ-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1 μg) effectively alleviated Aβ1–42 (20 μg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aβ1–42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aβ-induced deficits in learning and memory and the maintenance of L-LTP.     

N-Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation

Pyroglutamate (pGlu)-modified amyloid peptides have been identified in sporadic and familial forms of Alzheimer's disease (AD) and the inherited disorders familial British and Danish Dementia (FBD and FDD). In this study, we characterized the aggregation of amyloid-β protein Aβ37, Aβ38, Aβ40, Aβ42 and ADan species in vitro, which were modified by N-terminal pGlu (pGlu-Aβ3-x, pGlu-ADan) or possess the intact N-terminus (Aβ1-x, ADan). The pGlu-modification confers rapid formation of oligomers and short fibrillar aggregates. In accordance with these observations, the pGlu-modified Aβ38, Αβ40 and Αβ42 species inhibit hippocampal long term potentiation of synaptic response, but pGlu-Aβ3-42 showing the highest effect. Among the unmodified Aβ peptides, only Aβ1-42 exhibites such propensity, which was similar to pGlu-Aβ3-38 and pGlu-Aβ3-40. Likewise, the amyloidogenic peptide pGlu-ADan impaired synaptic potentiation more pronounced than N-terminal unmodified ADan. The results were validated using conditioned media from cultivated HEK293 cells, which express APP variants favoring the formation of Aβ1-x, Aβ3-x or N-truncated pGlu-Aβ3-x species. Hence, we show that the ability of different amyloid peptides to impair synaptic function apparently correlates to their potential to form oligomers as a common mechanism. The pGlu-modification is apparently mediating a higher surface hydrophobicity, as shown by 1-anilinonaphtalene-8-sulfonate fluorescence, which enforces potential to interfere with neuronal physiology.     

Expression and localization of ionotropic glutamate receptor subunits in the goldfish retina—an in situ hybridization and immunocytochemical study

The expression and distribution of AMPA, kainate and NMDA glutamate receptor subunits was studied in the goldfish retina. For the immunocytochemical localization of the AMPA receptor antisera against GluR2, GluR2/3 and GluR4 were used, and for in situ hybridization rat specific probes for GluR1 and GluR2 and goldfish specific probes for GluR3 and GluR4 were used. The localization of the low affinity kainate receptor and NMDA receptor was studied using antisera against GluR5-7 and NR1. All AMPA receptor subtypes were demonstrated to be present in the goldfish retina both by immunocytochemistry and in situ hybridization. In situ hybridization revealed expression of all AMPA receptors subunit at the inner border of the INL. Only GluR3 was also strongly expressed in the outer border of the INL. Some of the ganglion cells displayed a strong signal for GluR1, GluR3 and GluR4. GluR1-immunoreactivity was present in subsets of bipolar, amacrine, and ganglion cells. GluR2 and GluR2/3-immunoreactivity was mainly localized in the outer plexiform layer. GluR2 and GluR2/3-immunoreactivity are associated with the photoreceptor synaptic terminals. GluR4-immunoreactivity is present on Müller cells in the inner retina and on dendrites of bipolar cells in the OPL, whereas GluR5-7-immunoreactivity was prominently present on horizontal cell axon terminals. Finally, NR1-immunoreactivity was confined to amacrine cells, the inner plexiform layer and ganglion cells. This study shows that there is a strong heterogeneity of glutamate receptor subunit expression in the various layers of the retina. Of the AMPA receptor subunits GluR3 seems to be expressed the most widely in all layers with strong glutamatergic synaptic interactions whereas all the other subunits seem to have a more restricted expressed pattern.     

Are fear memories made and maintained by the same NMDA receptor-dependent mechanisms?

A recent finding indicates that inducible knockout of the NR1 NMDA receptor subunit promotes the loss of fear memories formed months earlier. One view is that posttraining NMDA receptor activation protects modified synapses from "synaptic drift." An alternative view is that NMDA receptors help maintain appropriate connectivity in memory-encoding networks.     

Do different rates of gene flow underlie variation in phenotypic and phenological clines in a montane grasshopper community?

Species responses to environmental change are likely to depend on existing genetic and phenotypic variation, as well as evolutionary potential. A key challenge is to determine whether gene flow might facilitate or impede genomic divergence among populations responding to environmental change, and if emergent phenotypic variation is dependent on gene flow rates. A general expectation is that patterns of genetic differentiation in a set of codistributed species reflect differences in dispersal ability. In less dispersive species, we predict greater genetic divergence and reduced gene flow. This could lead to covariation in life‐history traits due to local adaptation, although plasticity or drift could mirror these patterns. We compare genome‐wide patterns of genetic structure in four phenotypically variable grasshopper species along a steep elevation gradient near Boulder, Colorado, and test the hypothesis that genomic differentiation is greater in short‐winged grasshopper species, and statistically associated with variation in growth, reproductive, and physiological traits along this gradient. In addition, we estimate rates of gene flow under competing demographic models, as well as potential gene flow through surveys of phenological overlap among populations within a species. All species exhibit genetic structure along the elevation gradient and limited gene flow. The most pronounced genetic divergence appears in short‐winged (less dispersive) species, which also exhibit less phenological overlap among populations. A high‐elevation population of the most widespread species, Melanoplus sanguinipes, appears to be a sink population derived from low elevation populations. While dispersal ability has a clear connection to the genetic structure in different species, genetic distance does not predict growth, reproductive, or physiological trait variation in any species, requiring further investigation to clearly link phenotypic divergence to local adaptation.     

Are polyamines involved in the induction and regulation of the Crassulacean acid metabolism?

Leaves of plants with Crassulacean acid metabolism (CAM) were analyzed for variation in the content of polyamines in connection with the metabolism of malic acid in the dark and in the light, and with the induction of full-CAM activity. Under conditions (long days) resulting in extremely low CAM activity, young leaves of K. blossfeldiana have very low content in the polyamine-precursor arginine and in putrescine. The content in these two substances was increased dramatically by full-CAM induction with short days. During the course of the night/day cycle two peaks of putrescine content were observed in leaves of Kalanchoe blossfeldiana Poelln. Tom Thumb performing full-CAM operation: a large increase occurs toward the end of the day and the first half of the night, and its kinetics corresponds to the increase in the rate of malic acid synthesis; another peak, very sharp, appears during the first hours of the day, concomitant with the time of release of malic acid from the vacuole into the cytoplasm. In the case of Bryophyllum daigremontianum Berger similar variations were observed for the content in spermidine. These results support the hypothesis that polyamines could be involved in countering the tendency toward acidification of the cytoplasm at those moments of CAM operation at which the local concentration of malic acid is increased (i.e., during active synthesis in the dark and during the efflux from the vacuole in the light).Abbreviation CAM Crassulacean acid metabolism     

Determination of GABAAα1 and GABAB1 receptor subunits expression in tissues of gilts during the late gestation

GABA_Aα1 and GABA_B1 receptor subunits are responsible for most behavioral, physiological and pharmacological effects of GABA receptors. We investigated the expression of GABA_Aα1 and GABA_B1 receptor subunits in different tissues of gilts during late pregnancy in hot summer. The mRNA abundance of GABA_Aα1 receptor subunit in different tissues of gilts at d 90 and d 110 of gestation was as follows: d 90: brain > lung > liver > ovary > spleen > kidney > heart; d 110: brain > lung > spleen > liver > ovary > kidney > heart. And, the mRNA abundance of GABA_B1 receptor subunit was as follows: d 90: spleen > lung > brain > kidney > ovary > liver > heart; d 110: spleen > lung > kidney > brain > ovary > liver > heart. The results in this trial indicated that the GABA_Aα1 receptor subunit was abundantly expressed in brain, while GABA_B1 receptor subunit was abundant in spleen and lung of gilts during late gestation. There were no gestation stage-dependent effects on GABA_Aα1 and GABA_B1 receptor subunits expression in all tissues.     

What is the clinical relevance of different lung compartments?

The lung consists of at least seven compartments with relevance to immune reactions. Compartment 1 - the bronchoalveolar lavage (BAL), which represents the cells of the bronchoalveolar space: From a diagnostic point of view the bronchoalveolar space is the most important because it is easily accessible in laboratory animals, as well as in patients, using BAL. Although this technique has been used for several decades it is still unclear to what extent the BAL represents changes in other lung compartments. Compartment 2 - bronchus-associated lymphoid tissue (BALT): In the healthy, BALT can be found only in childhood. The role of BALT in the development of the mucosal immunity of the pulmonary surfaces has not yet been resolved. However, it might be an important tool for inhalative vaccination strategies. Compartment 3 - conducting airway mucosa: A third compartment is the bronchial epithelium and the submucosa, which both contain a distinct pool of leukocytes (e.g. intraepithelial lymphocytes, IEL). This again is also accessible via bronchoscopy. Compartment 4 - draining lymph nodes/Compartment 5 - lung parenchyma: Transbronchial biopsies are more difficult to perform but provide access to two additional compartments - lymph nodes with the draining lymphatics and lung parenchyma, which roughly means "interstitial" lung tissue. Compartment 6 - the intravascular leukocyte pool: The intravascular compartment lies between the systemic circulation and inflamed lung compartments. Compartment 7 - periarterial space: Finally, there is a unique, lung-specific space around the pulmonary arteries which contains blood and lymph capillaries. There are indications that this "periarterial space" may be involved in the pulmonary host defense. All these compartments are connected but the functional network is not yet fully understood. A better knowledge of the complex interactions could improve diagnosis and therapy, or enable preventive approaches of local immunization.