Retrograde adaptive resonance theory based on the role of nitric oxide in long-term potentiation

Adaptive resonance theory (ART) demonstrates how the brain learns to recognize and categorize vast amounts of information by using top–down expectations and attentional focusing. ART 3, one member of the ART family, embeds the computational properties of the chemical synapse in its search process, but it converges slowly and is lack of stability when being applied in pattern recognition and analysis. To overcome these problems, Nitric Oxide (NO), which serves as a newly discovered retrograde messenger in Long-Term Potentiation (LTP), is introduced in retrograde adaptive resonance theory (ReART) model presented in this paper. In the presented model a novel search hypothesis is proposed to incorporate angle and amplitude information of an external input vector to decide whether the input matches the long-term memory (LTM) weights of an active node or not, and the embedded NO retrograde mechanism makes the search procedure a closed loop, which improves the stability and convergence speed of the transmitter releasing mechanism in a synapse. To make the model more adaptive and practical, a forgetting mechanism is built to improve the weights updating process. Experimental results indicate that the proposed ReART model achieves low error rate, fast convergence and self-organizing weights regulation. Action Editor: Christiane Linster     

一氧化氮在长时程增强中作用的研究进展

长时程增强（ＬＴＰ）是神经突触可塑性和突触传递的一种表现形式,被认为是学习和记忆的细胞学基础,但有关ＬＴＰ的形成机制仍存有争论。普遍认为ＬＴＰ的维持需要逆行信使的参与,本文就ＮＯ作为逆向信使以及其在ＬＴＰ学习和记忆中的作用做了简要综述。     

Circadian regulation of hippocampal long-term potentiation

The goal of this study is to investigate the possible circadian regulation of hippocampal excitability and long-term potentiation (LTP) measured by stimulating the Schaffer collaterals (SC) and recording the field excitatory postsynaptic potential (fEPSP) from the CA1 dendritic layer or the population spike (PS) from the soma in brain slices of C3H and C57 mice. These 2 strains of mice were of interest because the C3H mice secrete melatonin rhythmically while the C57 mice do not. The authors found that the magnitude of the enhancement of the PS was significantly greater in LTP recorded from night slices compared to day slices of both C3H and C57 mice. They also found significant diurnal variation in the decay of LTP measured with fEPSPs, with the decay slower during the night in both strains of mice. There was evidence for a diurnal rhythm in the input/output function of pyramidal neurons measured at the soma in C57 but not C3H mice. Furthermore, LTP in the PS, measured in slices prepared during the day but recorded during the night, had a profile remarkably similar to the night group. Finally, PS recordings were carried out in slices from C3H mice maintained in constant darkness prior to experimentation. Again, the authors found that the magnitude of the enhancement of the PS was significantly greater in LTP recorded from subjective night slices compared to subjective day slices. These results provide the 1st evidence that an endogenous circadian oscillator modulates synaptic plasticity in the hippocampus.     

Mechanism of TrkB-mediated hippocampal long-term potentiation

The TrkB receptor tyrosine kinase and its ligand, BDNF, have an essential role in certain forms of synaptic plasticity. However, the downstream pathways required to mediate these functions are unknown. We have studied mice with a targeted mutation in either the Shc or the phospholipase Cgamma (PLCgamma) docking sites of TrkB (trkB(SHC/SHC) and trkB(PLC/PLC) mice). We found that hippocampal long-term potentiation was impaired in trkB(PLC/PLC) mice, but not trkB(SHC/SHC) mice. BDNF stimulation of primary neurons derived from trkB(PLC/PLC) mice fully retained their ability to activate MAP kinases, whereas induction of CREB and CaMKIV phosphorylation was strongly impaired. The opposite effect was observed in trkB(SHC/SHC) neurons, suggesting that MAPKs and CREB act in parallel pathways. Our results provide genetic evidence that TrkB mediates hippocampal plasticity via recruitment of PLCgamma, and by subsequent phosphorylation of CaMKIV and CREB.     

Postsynaptic control of hippocampal long-term potentiation

Long-term potentiation (LTP) in the hippocampus has the property of cooperativity, i.e. greater potentiation is produced if a larger number of afferent fibres is tetanized. The possible involvement of postsynaptic mechanisms in this process was investigated in the CA1 area of the hippocampal slice preparation. Following blockade of postsynaptic inhibition by GABA antagonists, e.g. picrotoxin, the induction of LTP was greatly facilitated. In picrotoxin-treated slices, LTP was induced in a pathway stimulated by single volleys, if these occurred in conjunction with brief tetanic activation of other afferents. This interaction operated over a short period of time (less than 50 ms) and was also present if the inputs were separated in space (cooperativity between inputs to basal and apical dendrites). LTP could be induced by pairing single volley synaptic activation and intracellularly injected depolarizing current pulses, the timing requirements being similar to those observed in the extracellular "conjunction studies". Previous studies have suggested that glutamate receptor channels of the N-methyl-D-aspartate (NMDA) type are somehow involved in LTP induction. Evidence presented here shows that activation leading to LTP evokes a potential which is sensitive to the NMDA receptor blocker 2-amino-5-phosphonovalerate (APV), indicating passage of current through NMDA receptor channels. The results suggest that hippocampal LTP depends on simultaneous presynaptic transmitter release and postsynaptic depolarization in a manner analogous to the model proposed by HEBB (1949) for associative learning. Furthermore, it is proposed that the required pre- and postsynaptic interaction is handled by the NMDA receptor channel complex, which is known to have the required voltage and transmitter sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide acts as a retrograde messenger during long-term potentiation in cultured hippocampal neurons

We examined long-term potentiation (LTP) at synapses between hippocampal neurons in dissociated cell culture following presynaptic, postsynaptic, or extracellular application of a nitric oxide (NO) scavenger, an inhibitor of NO synthase, and a membrane-impermeant NO donor that releases NO only upon photolysis with UV light. Our results indicate that NO is produced in the postsynaptic neuron, travels through the extracellular space, and acts directly in the presynaptic neuron to produce long-term potentiation, supporting the hypothesis that NO acts a retrograde messenger during LTP.     

The mechanism of potentiation of the glutamate-induced neurotoxicity by serum albumin. A possible role of nitric oxide

Potentiation of the delayed (Glu)-induced neurotoxicity by serum albumin (SA) was studied in experiments with cultured cerebellar granule cells. The delayed neuronal death (DND) was evaluated by counting neurons containing or excluding Trypan Blue 4 h after treatment with Glu. Cytoplasmic Ca2+ ([Ca2+]i) was measured in individual Fura-2-loaded neurons. It was shown that a 15-min application of bovine SA (4 mg/ml) together with Glu (100 microM, 10 microM glycine, Mg2+-free solution) enhanced DND in the culture 1.7 times (43.1+/-3.1%) with respect to the effect induced by Glu alone (24.6+/-0.6%). The bovine SA application did not change the dynamics of [Ca2+]i response during a short-term (1 min) and long-term (15 min) Glu-treatment. DND was prevented by simultaneous application of Glu and inhibitor of NO-synthase N omega-nitro-L-arginine methyl ester (L-NAME), 100 microM) (10.8+/-1.0%) as well as by the application of Glu with SA and L-NAME (9.8+/-1.2%). In order to evaluate the role of nitric oxide (NO) in the SA effect, the cells were incubated for 15 min with the NO-donors sodium nitroprusside (SNP, 10 and 100 microM) and sodium nitrite (NaNO2, 10 and 100 microM) together with SA and in its absence. SA also greatly enhanced the DND induced by SNP and NaNO2. Thus, the DND after simultaneous treatment with SA and SNP was 16.3+/-2.5% (10 microM) or 29.6+/-2.1% (100 microM), and 9.6+/-0.8% (10 microM) and 19.7+/-2.1% after treatment with SNP alone. Exposure to SA together with NaNO2 led to the DND increase up to 26.5+/-1.9% (10 microM) and 37.7+/-3.5% (100 microM) in comparison with 7.4+/-2.0% (10 microM) and 18.9+/-0.8% (100 microM) in experiments with NaNO2 alone. Taking into account the ability of NO and NO2 to oxidize unsaturated fatty acids and the ability of SA to bind them after their hydrolytic removal, we suggested that the SA-induced potentiation of Glu neurotoxicity resulted from exacerbation of the toxic effects of NO and other trace radicals on the neuronal membranes. This hypothesis was supported by the finding that SA also enhanced the neurotoxicity of the lipid prooxidant FeCl2. The simultaneous 15-min application of FeCl2 (10 microM) and SA caused a 51.5+/-4.0% increase in DND, which exceeded 2.4 times the effect produced by FeCl2 alone (21.3+/-2.3%).     

Involvement of mitogen-activated protein kinase in hippocampal long-term potentiation

Mitogen-activated protein kinase (MAPK) cascade classically is thought to be involved in cellular transformation, including proliferation and differentiation. Recent behavioral studies suggest that MAPK may also have a role in learning and memory. Long-term potentiation (LTP), a candidate mechanism for learning and memory, has at least two distinct temporal phases: an early phase (E-LTP) which lasts for 1–2 h and a late phase (L-LTP) which can persist 3 h. Here, we report that PD 098059, a selective inhibitor of MAPK cascade, attenuates L-LTP induced by bath application of forskolin without affecting basal synaptic transmission. This effect was mimicked by direct injection of animals with MAPK antisense oligonucleotide into the hippocampal CA1 region. MAPK activity measured by using a synthetic peptide corresponding to the sequence surrounding the major site of phosphorylation of the myelin-basic protein by MAPK was enhanced by forskolin. The same antisense treatment also completely inhibited the increased MAPK activity. These results demonstrate an involvement of MAPK in the induction of L-LTP in the hippocampal CA1 neurons.     

The role of nitric oxide in cancer

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including va-sodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic pro     

The role of nitric oxide in cancer

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including vasodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelia (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties. Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis by upregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53, poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understanding at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease.     

The role of nitric oxide in cancer

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including va-sodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases(NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interest-ingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting theetiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and hasbeen associated with tumour grade, proliferation rate and expression of important signaling componentsassociated with cancer development such as the oestrogen receptor. It appears that high levels of NOSexpression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumorcells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxicallytherefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties.Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis byupregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53,poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understand-ing at the molecular level of the role of NO in cancer will have profound therapeutic implications for thediagnosis and treatment of disease.     

植物中一氧化氮的生理作用

No是一种易扩散的生物活性分子,是生物体内重要的信号分子。植物细胞通过NO合酶,硝酸还原酶,或非生化反应途径产生NO。NO参与植物生长发育调控和对生物和非生物胁迫的应答反应。主要通过讨论No的产生,对植物生长发育的影响及在抗逆反应中的信号调节来阐述No在植物中的作用。     

The role of nitric oxide in cancer

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including va-sodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interest-ingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties.Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis by upregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53,poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understand-ing at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease.     

Caspase-3 inhibition blocks long-term potentiation in hippocampal slices

Incubation of hippocampal slices with Z-DEVD-FMK, a specific inhibitor of caspase-3, elicits a time dependent decrease in long-term potentiation (LTP). After 4 hours or later after the incubation with Z-DEVD-FMK the tetanization fails to induce LTP. However, Z-DEVD-FMK does not affect basal indices of synaptic plasticity and short-term plasticity (population spike amplitudes and paired pulse facilitation). The results are the first evidence for the involvement of caspase-3-mediated mechanisms in long-term potentiation phenomenon.     

The physiological role of nitric oxide

The review is devoted to exposition of a physiological role of a nitric oxide (NO), free radical gas, in various physiological functions. The number of those NO involvements is extremely high: bacteriocidal, cytotoxic and antitumor leukocyte effects, a relaxation of smooth-muscle cells of both vessels and gastrointestinal tract, the name just a few. The scheme of NO formation in various biological systems and its targets were shown and neuromodulator functions of NO in a brain were analyzed by the review presented. The findings of own researches on a role of NO in function of neuro-muscular synapse were included by the authors.     

The maintenance of hippocampal long-term potentiation is paralleled by a dopamine-dependent increase in glycoprotein fucosylation.

Induction of long-term potentiation (LTP) in hippocampal slices of rats caused an increase in both protein synthesis and glycoprotein fucosylation by 38 and 34%, respectively. The enhanced incorporation of [3H]fucose into glycoproteins observed 1 h after tetanization was abolished in the presence of the dopamine D1 receptor antagonist SCH23390 during stimulation whereas the LTP-induced increase of protein synthesis was not influenced by this drug. The enhanced insertion of [3H]fucose into hippocampal glycoproteins 1 h after tetanization was paralleled by an increase in the activity of the fucose metabolizing enzyme, fucokinase. In contrast no changes in protein and glycoprotein synthesis were detectable 5 h after tetanization of the slices. The results provide evidence that in addition to an enhanced protein synthesis a dopamine (D1) mediated increase in glycoprotein fucosylation is necessary for the maintenance of the late stage of LTP.     

The early role of nitric oxide in evolution

Nitric oxide (NO), which today serves many different purposes in regulating complex cellular functions, must have played a crucial role in the early stages of the evolution of life. The formation of NO may have been a critical defence mechanism for primitive microorganisms at a time when life faced the problem of rising atmospheric levels of ozone (03) formed upon photolysis of oxygen (Oz), which occurred shortly after the development of respiration in cyanobacteria. The production of NO by organisms would have allowed neutralization of toxic 03 by chemical reaction outside the cell, thus acting as a protective mechanism against oxidative destruction, allowing evolutionary advantage. Later, NO production might have allowed the control of reactive OZ species within cells before the development of specific electron-accepting enzymes. The pathway of NO formation was then consequently developed further to serve other useful functions. Although mammalian cells produce NO from L-arginine, the origin of this ability might have arisen from the essential process of either nitrification or denitrification in prokaryotic cells.     

Low intensity tetanic stimulation induces long-term potentiation in hippocampal neurons

A minimal intensity of the stimulation necessary for the induction of long-term potentiation of synaptic transmission (LTP) was investigated by intracellular recording in guinea pig in vitro hippocampal slices. High frequency stimulation of afferent fibres at intensities evoking in CA 1 neurons control excitatory postsynaptic potentials (EPSPs) of amplitudes 1-5 mV, resulted usually in a long-lasting increase in response amplitude. LTP was not observed at lower stimulus strength. The coactivation of a certain, though small number of synaptic contacts is thus necessary for the production of LTP.     

Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice

Protein tyrosine phosphatase delta (PTPdelta) is a receptor-type PTP expressed in the specialized regions of the brain including the hippocampal CA2 and CA3, B lymphocytes and thymic medulla. To elucidate the physiological roles of PTPdelta, PTPdelta-deficient mice were produced by gene targeting. It was found that PTPdelta-deficient mice were semi-lethal due to insufficient food intake. They also exhibited learning impairment in the Morris water maze, reinforced T-maze and radial arm maze tasks. Interestingly, although the histology of the hippocampus appeared normal, the magnitudes of long-term potentiation (LTP) induced at hippocampal CA1 and CA3 synapses were significantly enhanced in PTPdelta-deficient mice, with augmented paired-pulse facilitation in the CA1 region. Thus, it was shown that PTPdelta plays important roles in regulating hippocampal LTP and learning processes, and that hippocampal LTP does not necessarily positively correlate with spatial learning ability. To our knowledge, this is the first report of a specific PTP involved in the regulation of synaptic plasticity or in the processes regulating learning and memory.