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Meta-modulation of hippocampal excitatory transmission by adenosine in rats: from a physiological situation to hypoxic/ischemic insult 

By etavares On 30 April, 2011 Science Space | 2011 Comments Off on Meta-modulation of hippocampal excitatory transmission by adenosine in rats: from a physiological situation to hypoxic/ischemic insult  No tags

In 1791 Luigi Galvani revealed the electrical nature of nerve impulses in frogs’ neuromuscular joints, when he published his masterwork De viribus electricitatis in motu musculari commentarius [1]. Strongly influenced by Galvani’s work, the scientific community defended the concept of bio-electricity up to the beginning of the 20th century, when Ramón y Cajal’s illustrations questioned the possibility of electrical transmission between communicating neurons through perceptible intervals. Afterwards, Otto Loewi’s experiments in vagus nerve preparations led to the discovery of the first neurotransmitter, acetylcholine [2]. This was the beginning of the neurotransmitter concept, an endogenous chemical substance capable of ensuring the correct transmission of information between one neuron and another cell in the body. Recognition of glutamate as the main excitatory neurotransmitter only occurred in the 1950s, when Jeffrey Watkins contributed to this field by identifying distinct types of ionotropic glutamate receptors. [3], of which AMPA type receptors are the main mediators of rapid excitatory transmission in the central nervous system.

By allowing variation of the response capacity of the postsynaptic neuron to the glutamate released by the afferent neuron, regulation of the AMPA function ensures significant changes in the efficiency of synaptic transmission that are inherent to the maturation of neural networks with development, as well as to synaptic plasticity phenomena. In addition, these receptors are key molecules in excitotoxicity situations, which hypoxic or ischemic insults are examples of. In those situations, the increase in extracellular concentration of glutamate and the superactivation of its receptors encourages the unregulated flow of calcium and activates cell death cascades. Unfortunately, the neuroprotective potential of AMPA antagonists in animal models of brain ischemia has not found parallel in clinical trials carried out so far. [4]. As an alternative, strategies for the pharmacological modulation of the AMPA function may be of interest from a therapeutic stance. Accordingly, the present work aimed to investigate the possibility of adenosine-mediated modulation of the postsynaptic AMPA component, because it is an ubiquitous neuromodulator whose multiple actions ensure the balance between incoming and used energy substrates in excitable tissues [5]. To this effect, patch-clamp recordings of currents mediated by AMPA receptors were made in pyramidal cells of the CA1 area of the hippocampus.

Particularly prone to reflect changes in synaptic efficiency according to levels of activity, this neural population is also particularly susceptible to death by apoptosis following ischemia. We have noted that using an adenosine A2A receptor agonist (CGS21680) lead to a significant increase in the amplitude of AMPA currents, which was lost in the presence of a protein kinase A inhibitor (PKA). It is known that the PKA phosphorylation of AMPA receptors enables regulating neuronal membrane traffic. Resorting to biotinylation trials to selectively evaluate the membrane receptor levels, we found that the latter increased following administering CGS21680. Afterwards, and in order to ascertain the functional impact of this modulation, we used a high frequency afferent stimulation protocol capable of evoking long term potentiation (LTP) of the synaptic transmission, considered to be the cellular substrate in the formation of new memories. We noted that this form of plasticity was facilitated after a brief course of treatment with CGS21680. In addition, blockade of the A2A receptors reduced, by itself, the magnitude of the LTP, which suggests that it is an endogenous regulatory mechanism. Accordingly, it is possible to infer that in situations of sudden increase of extracellular adenosine caused by exacerbated neuronal activity, the activation of A2A receptors facilitates the PKA phosphorylation of AMPA receptors, which increases their availability in membrane reserves and corresponding recruitment to synapse, thus strengthening synaptic transmission.

Curiously, these conditions of exacerbated neuronal activity and the extracellular accumulation of adenosine are also present in the initial stages of ischemic insults. We also know that exposure to transitory hypoxic/ischemic insults brings about a persistent increase in synaptic efficiency that shares many of the mechanisms inherent to LTP expression, including a functional gain of the postsynaptic AMPA component. With the aim of investigating the involvement of A2A receptors in this process, we compared the effects of brief ischemic insults [6] in the presence and absence of a receptor selective antagonist (SCH58261). As noted by other authors, the inhibition of synaptic transmission caused by the insult was followed by a gradual recovery of the postsynaptic response, up to values significantly higher than the initial ones. This type of ischemia-induced plasticity was totally abolished both by the previous blockade of A2A receptors and by the antagonism of a subclass of AMPA receptors permeable to calcium. Thus, these results reveal a new mechanism of adenosine neuromodulation, and also demonstrate the presence of new common features between physiological and “pathological” forms of plasticity. In this context, it will be of utmost interest to clarify the role played by ischemia-induced plasticity processes, given that, whether they contribute to aggravating damages caused by excitotoxicity or are involved in the formation of new synaptic contacts able to recover some of the lost circuits in regions most affected by ischemic accidents, is still subject to controversy. From the viewpoint of the latter hypothesis, it may also be important to invest in neurogenerative strategies that use drugs that modulate (adaptive) plasticity triggered by ischemia.

The results described above are part of the research carried out as part of my PhD thesis, which was recently submitted to FCT for appreciation. The work was supervised by Professors Joaquim Alexandre Ribeiro and Ana Maria Sebastião, to whom I express my deep gratefulness. For a detailed viewing of the results, please see Dias et al., 2010
(here)

 

Raquel Baptista Dias
Institute of Pharmacology and Neurosciences, Faculty of Medicine
Neuroscience Unit, Institute of Molecular Medicine
rdias@fm.ul.pt
_____________________
Bibliografia

[1] Galvani L (1791) De viribus electricitatis in motu musculari commentarius. Bon Sci Art Inst Acad Comm 7:363–418
[2] Loewi O (1921) Über humorale Übertragbarkeit der Herznerven-wirkung. Pflügers Archiv189: 239-242
[3] Curtis DR, Watkins JC (1961) Analogues of glutamic and gamma-amino-n-butyric acids having potent actions on mammalian neurones. Nature 191:1010-1011
[4] Mattes H, Carcache D, Kalkman HO, Koller M (2010) alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists: from bench to bedside. J Med Chem 53: 5367-5382
[5] Sebastião AM, Ribeiro JA (2000) Fine-tuning neuromodulation by adenosine. Trends Pharmacol Sci 21: 341-634
[6] Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403: 316-321

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Index - News # 20 | mar/abr. 2011
 Editorial Note
 Camilla, Duchess of Cornwall, visit IMM
 New@FMUL New Editorial Team
 The Harvard Medical School Portugal Program brings health to social networks.
 What now, Portugal?” – RTP Programme “Pros and Cons” at the University of Lisbon
 SPUL organises the first training course
 Interview with Professor Alexandre Ribeiro – Pharmacology and Neuroscience Institute’s Director
 FUTURÁLIA: “This is your life! Find your own way”
 Cid dos Santos Cultural Soiree
 Curricular Reform at the Faculty of Medicine of the University of Lisbon
 Ceremony of the 100th Anniversary of the University of Lisbon
 Consentimento informado e Esclarecido – Debates de Reflexão da Associação dos Antigos Alunos FMUL
 The Administrative Branches Coordinating Unit – presents the project to FMUL’s Newsletter
 Book of the Month
 3rd Post-Graduate Refresher Course “Ethical Decisions In End Of Life” – 14-16 April
 Provas Académicas na Faculdade de Medicina da Universidade de Lisboa
 Lecturers’ Participation in Academic Examinations Panels in other institutions by 24 March 2011
 Scientific Research Projects 2009/2010 – Neurosciences Area
 ONCOLOGY SERIES Seminars- Interview with Professor Luís Costa
 Publications FMUL/HSM/IMM
 Modulation of hippocampal GABAergic transmission by adenosine – Summary of ongoing project 
 Regulation of the GAT-1 transporter in neuronal cells: action of the Brain-Derived Neurotrophic Fact
 Modulation of GABA transport – Effect of adenosine on GAT-1 and GAT-3 mediated GABA reuptake  
 Meta-modulation of hippocampal excitatory transmission by adenosine in rats: from a physiological situation to hypoxic/ischemic insult 
 Relationship between depression and dementia: clinical and animal behaviour studies
 Neuroscience Debate in the Second Conference Falar Global (Talking Globally)
 Biorrythms and School Underachievement: a few opinions and thoughts
 Social networks and social movements
 Sports, Culture and Wellness at the University of Lisbon – Activities in April
 The European Documentation Center of The University of Lisbon publishes Newsletter
 Instituto Confúcio
 Science and Health Research
 Dia Mundial da Voz – 16 de Abril
 XII Meeting of the Portuguese Society for Neurosciences – May 26-28, 2011
 Seminar Oncology Series – Targeted Therapy for Advanced Renal Cell Carcinoma – 5 de Maio
 Prémio Água é Saúde – Candidaturas até 1 de Junho
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100 AnosPropriedade e Edição: Faculdade de Medicina da Universidade de Lisboa NIPC: 502662875  Periodicidade: Mensal  Diretor: Prof. Doutor Fausto J. Pinto Conselho Editorial: Prof. Doutor Fausto J. Pinto, Profª. Doutora Ana Sebastião, Prof. Doutor Mamede de Carvalho, Prof. Doutor António Vaz Carneiro, Prof. Doutor Miguel Castanho, Dr. Luís Pereira  Equipa Editorial:  Ana Raquel Moreira, Cristina Bastos, Isabel Varela, Joana Sousa, Maria de Lurdes Barata, Rui Gomes, Sónia Teixeira  Colaboração:  Gabinete de Relações Públicas, Internacionais e Comunicação  Versão Inglesa: AP|PORTUGAL- Language Services  Conceção: Metatexto, Lda. e-mail: news@medicina.ulisboa.pt  Sede do Editor e Sede da Redação: Avenida Prof. Egas Moniz, 1649-028 Lisboa Estatuto Editorial Anotado na ERC 

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