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G protein-coupled receptor oligomerization is a concept which is changing the understanding of classical pharmacology. Both, oligomerization and functional interaction between adenosine A 2A, dopamine D 2 and metabotropic glutamate type 5 receptors have been demonstrated in the striatum. However, the transcriptional consequences of receptors co-activation are still unexplored. We aim here to determine the changes in gene expression of striatal primary cultured neurons upon isolated or simultaneous receptor activation. Interestingly, we found that 95 genes of the total analyzed (15,866 transcripts and variants) changed their expression in response to simultaneous stimulation of all three receptors. Among these genes, we focused on the β-synuclein (β-Syn) gene ( SCNB) . Quantitative PCR verified the magnitude and direction of change in expression of SCNB . Since β-Syn belongs to the homologous synuclein family and may be considered a natural regulator of α-synuclein (α-Syn), it has been proposed that β-Syn might act protectively against α-Syn neuropathology.

G protein-coupled receptors are known to form homo-and heteromers at the plasma membrane, but the molecular properties of these oligomers are relatively unknown. Here, we show a method that allows the diffusion of G protein-coupled receptors oligomers in the plasma membrane to be monitored in single cells by combining Bimolecular Fluorescence Complementation and Fluorescence Correlation Spectroscopy. With this approach we have measured, for the first time, the membrane diffusional characteristics of adenosine A(1) and A(2A) receptor homo-and heterodimers in Chinese Hamster Ovary cells. Interestingly, both homodimers display similar diffusion co-efficients (D) when expressed in living cells (D=5.0 and 4.8x10(-9) cm(2)/s, respectively) but the heterodimer formed by these receptors exhibit a significantly faster plasma membrane diffusion co-efficent (D=5.6x10(-9) cm(2)/s) when compared to the adenosine A(1) receptor tagged with the full-length yellow fluorescent protein (D=4.0x10(-9) cm(2)/s). Overall, these results demonstrate differences in plasma membrane diffusion between adenosine receptor homo-and heterodimers, providing new insights into the molecular plasticity of G protein-coupled receptor oligomerization.

A wide range of data in the literature suggests that environmental enrichment has beneficial effects on various cognitive parameters in rodents. However, the magnitude of these effects and their persistence after the cessation of enrichment vary markedly across studies, with the use of different enrichment protocols probably playing a significant role in this variation. Using an open field habituation task as a paradigm, we investigate whether the duration and starting age of environmental enrichment affect the magnitude and persistence of its behavioral effects on male CF-1 albino mice. Our data shows that, at least in our protocol, (a) environmental enrichment, both after weaning and in early adulthood, decreases locomotion in an open field task, probably by increasing habituation; (b) a minimum enrichment period is necessary to induce this behavioral effect; (c) the effect of enrichment can persist at least partially for many months after its cessation; and (d) the degree of this persistence appears to be somewhat greater in animals exposed to longer durations of enrichment.

The reconsolidation hypothesis, which predicts that consolidated memories become labile and sensitive to amnestic agents upon reactivation, has been one of the most debated topics in memory research over recent years. One of the main criticisms to this hypothesis is the fact that some studies have shown the effects of "reconsolidation blockade" to be transient. Here we show that muscimol inactivation of the dorsal hippocampus following memory reactivation produces a reversible impairment of step-down inhibitory avoidance memory in rats. Moreover, we show that the reversal of this effect is dependent on the passage of time, and not on repeated testing. The implications of the findings to the interpretation of the phenomenon of transient retrieval impairment induced by post-reactivation pharmacological interventions on memory systems are discussed.

Studies have shown that supplementation with berries rich in anthocyanins are effective in reducing oxidative stress associated with aging, and are beneficial in reversing age-related neuronal and behavioral changes. However, there are few reports on other biological activities of these polyphenols, such as genoprotective effects. The present experiments were performed to study the possible effects of 30-day administration of a lyophilized extract of Vaccinium ashei berries on cognitive performance using step-down inhibitory avoidance, open-field habituation and elevated plus-maze tasks, as well as on DNA damage in the hippocampus and cerebral cortex. The present study showed that the extract significantly enhanced long-term memory in the inhibitory avoidance task, induced an increase in the number of crossings during open-field habituation and had an anxiolytic effect in the elevated plus-maze task. Moreover, the extract reduced oxidative DNA damage in brain tissue in vitro. These results suggest that supplementation with V. ashei berries to mice improves performance on memory tasks and has a protective effect on DNA damage, possibly due to the antioxidant activity of polyphenols, including anthocyanins.

Although many studies have investigated the function of cellular prion protein (PrPc), its physiologic role remains elusive. PrPc null mice have been reported to develop normally and to show normal performance in most behavioural tests. In the present study we investigated whether this also holds true after episodes of acute stress. PrPc gene ablated (Prnp0/0) and wild-type mice were subjected to restraint stress, electric foot shock, or swimming and compared with non-stressed animals. Immediately after the stressful situation, the anxiety levels and locomotion of the animals were measured using plus-maze and open-field tests. Among non-stressed animals, there was no significant difference in performance between Prnp0/0 and wild type animals in either test. However, after acute stress provoked by a foot shock or a swimming trial, Prnp0/0 animals showed a significant decrease in anxiety levels when compared with control animals. Moreover, after the swimming test, knockout mice presented decreased locomotion when compared to wild-type mice. Because of this observation, we also assessed both types of mice in a forced swimming test with the objective of better evaluating muscle function and found that Prnp0/0 animals presented reduced forced swimming capacity when compared to controls. As far as we know, this is the first report suggesting that cellular prion protein is involved in modulation of anxiety or muscular activity after acute psychic or physical stress.

We read with great interest the article by Orban et al.1xOrban, P.C., Chapman, P.F., and Brambilla, R. Trends Neurosci. 1999; 22: 38–44Abstract | Full Text | Full Text PDF | PubMed | Scopus (161)See all References1 because we too have recently found that the mitogen-activated protein kinase (MAPK) cascade is involved in the long-term memory of an inhibitory avoidance task (IA). The infusion of a specific MAPK kinase inhibitor, PD 098059, into the amygdala 3 h after training impaired IA retention in rats2xSee all References2. These data, together with the discovery that Ras–GRF (guanine-releasing factor)-null mice show impairment in plasticity in the amygdala and in an aversive learning task3xBrambilla, R. et al. Nature. 1997; 390: 281–286Crossref | PubMedSee all References3, suggests that the MAPK cascade has a crucial role both in the physiology and the development of the amygdala. We also found that, in the CA1 region of the hippocampus, the inhibition of MAPK kinase 3 h after training2xSee all References2, like that of protein kinase A (PKA)4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all References4, also impaired long-term IA retention. Meanwhile, Atkins et al. have demonstrated a requirement for MAPK activation in the hippocampus during fear-conditioning5xAtkins, C.M. et al. Nat. Neurosci. 1998; 1: 602–609Crossref | PubMedSee all References5, and MAPK activation is also required for the induction of LTP in the hippocampus6xEnglish, J.D. and Sweat, J.D. J. Biol. Chem. 1997; 272: 19103–19106Crossref | PubMed | Scopus (620)See all References6. As was indicated by Orban et al.1xOrban, P.C., Chapman, P.F., and Brambilla, R. Trends Neurosci. 1999; 22: 38–44Abstract | Full Text | Full Text PDF | PubMed | Scopus (161)See all References, 3xBrambilla, R. et al. Nature. 1997; 390: 281–286Crossref | PubMedSee all References, Ras–GRF-null mice have no impairment of LTP in the hippocampus and show normal behavior during spatial learning tasks; these animals, therefore, seem to be able to compensate the eventual MAPK cascade dysfunction in the hippocampus.When infused into the entorhinal cortex immediately or 3 h after training, PD 098059 (Ref. 2xSee all ReferencesRef. 2), like the PKA inhibitor4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all References4, also impaired IA. The similar post-training time window of effectiveness of the MAPK (Ref. 2xSee all ReferencesRef. 2) and PKA (Ref. 4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all ReferencesRef. 4) inhibitors in the CA1 region and the entorhinal cortex is coincident with the rise in cAMP levels, PKA activity and FOS levels4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all References4, which raises the possibility of crosstalk between the MAPK and PKA cascades in these structures. In fact, MAPK activation by the cAMP–PKA pathway has been demonstrated in PC12 cells7xVossler, M.R. et al. Cell. 1997; 89: 73–82Abstract | Full Text | Full Text PDF | PubMedSee all References7, while cAMP can stimulate neuronal MAPK through a PKA-independent mechanism8xKawasaki, H. et al. Science. 1998; 282: 2275–2279Crossref | PubMed | Scopus (905)See all References8.Other kinases can interact either directly or indirectly with the MAPK cascade, including protein kinase C (PKC)9xSeger, R. and Krebs, E.G. FASEB J. 1995; 9: 726–735PubMedSee all References9 and Ca2+/calmodulin-dependent protein kinases II (CaMKII)10xChen, H.J. et al. Neuron. 1998; 20: 895–904Abstract | Full Text | Full Text PDF | PubMed | Scopus (394)See all References10 and IV (CaMKIV)8xKawasaki, H. et al. Science. 1998; 282: 2275–2279Crossref | PubMed | Scopus (905)See all References, 11xSahyoun, N. et al. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 2643–2647Crossref | PubMedSee all References. Some of these kinses (PKC, CaMKII) have also been shown to be involved in the IA processing at different post-training times, depending on the brain structure studied4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all References4. It has been estimated that humans have as many as 2000 genes encoding protein kinases and 1000 genes encoding phosphatases12xHunter, T. Cell. 1995; 80: 225–236Abstract | Full Text PDF | PubMed | Scopus (2149)See all References12. This extensive repertoire of kinases and phosphatases forms a complex network of biological signaling pathways13xBhalla, U.S. and Iyengar, R. Science. 1999; 283: 381–387Crossref | PubMed | Scopus (1018)See all References13, which can contribute to the specific response of distinct brain regions during physiological processes (for example, memory), as well as in genetic (for example, inborn errors of metabolism) or acquired pathologies (for example, stroke, secondary epilepsy).