Biomedical subjects

Lionel Muller Igaz

Publications and source records attributed to Lionel Muller Igaz.

4 recordsLinked to original sources

PubMed2004

Gene expression during memory formation.

For several decades, neuroscientists have provided many clues that point out the involvement of de novo gene expression during the formation of long-lasting forms of memory. However, information regarding the transcriptional response networks involved in memory formation has been scarce and fragmented. With the advent of genome-based technologies, combined with more classical approaches (i.e., pharmacology and biochemistry), it is now feasible to address those relevant questions--which gene products are modulated, and when that processes are necessary for the proper storage of memories--with unprecedented resolution and scale. Using one-trial inhibitory (passive) avoidance training of rats, one of the most studied tasks so far, we found two time windows of sensitivity to transcriptional and translational inhibitors infused into the hippocampus: around the time of training and 3-6 h after training. Remarkably, these periods perfectly overlap with the involvement of hippocampal cAMP/PKA (protein kinase A) signaling pathways in memory consolidation. Given the complexity of transcriptional responses in the brain, particularly those related to processing of behavioral information, it was clearly necessary to address this issue with a multi-variable, parallel-oriented approach. We used cDNA arrays to screen for candidate inhibitory avoidance learning-related genes and analyze the dynamic pattern of gene expression that emerges during memory consolidation. These include genes involved in intracellular kinase networks, synaptic function, DNA-binding and chromatin modification, transcriptional activation and repression, translation, membrane receptors, and oncogenes, among others. Our findings suggest that differential and orchestrated hippocampal gene expression is necessary in both early and late periods of long-term memory consolidation. Additionally, this kind of studies may lead to the identification and characterization of genes that are relevant for the pathogenesis of complex psychiatric disorders involving learning and memory impairments, and may allow the development of new methods for the diagnosis and treatment of these diseases.

Amanitins↗

PubMed2003

Memory extinction requires gene expression in rat hippocampus.

Rats with cannulae in the dorsal CA1 region of the hippocampus were trained in one-trial step-down inhibitory avoidance, and submitted to four consecutive daily test sessions without the footshock. This produced extinction of the conditioned response in control animals. The bilateral infusion into the CA1 region of the dorsal hippocampus of two different inhibitors of gene transcription, DRB (80 microg/side) or alpha-amanitin (25 pg/side), or of the protein synthesis inhibitor, anisomycin (80 microg/side) blocked extinction of the CR. The treatments were effective when given 15 min before, but not 1 or 3h after the first test session. Retrieval itself was not affected by the drugs. The treatments did not affect general activity in an open field or anxiety levels measured in an elevated plus maze. The data indicate that gene transcription and protein synthesis are necessary at the time of the first test session in order to generate extinction. These requirements are to be expected from learning that involves new synaptic associations.

Amanitins↗

PubMed2002

Two time periods of hippocampal mRNA synthesis are required for memory consolidation of fear-motivated learning.

Information storage in the brain is a temporally graded process involving different memory types or phases. It has been assumed for over a century that one or more short-term memory (STM) processes are involved in processing new information while long-term memory (LTM) is being formed. It has been repeatedly reported that LTM requires de novo RNA synthesis around the time of training. Here we show that LTM formation of a one-trial inhibitory avoidance training in rats, a hippocampal-dependent form of contextual fear conditioning, depends on two consolidation periods requiring synthesis of new mRNAs. By injecting the RNA polymerase II inhibitors 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole or alpha-amanitin into the CA1 region of the dorsal hippocampus at various times before and after training, we found that hippocampal gene expression is critical in two time windows: around the time of training and 3-6 hr after training. Interestingly, these two periods of sensitivity to transcriptional inhibitors are similar to those observed using the protein synthesis inhibitor anisomycin. These findings underscore the parallel dependence of LTM formation of contextual fear on mRNA and protein synthesis in the hippocampus and suggest that the two time periods of anisomycin-induced amnesia depend at least in part on new mRNA synthesis.

Amanitins↗

PubMed2002

CRE-mediated transcriptional activation is involved in cAMP protection of T-cell receptor-induced apoptosis but not in cAMP potentiation of glucocorticoid-mediated programmed cell death.

Apoptosis of thymic cells induced by glucocorticoids (GC) and T-cell receptor (TCR) engagement are mutually antagonistic. We demonstrate that cAMP enhances GC and antagonizes TCR (anti-CD3) apoptosis on the same cell (DO-11.10 and 2B4.11 T-cell hybridomas). We analyzed the activity of several transcription factors in this cAMP dual, stimulus-dependent, regulatory action. Anti-CD3 increases kB-activity which is inhibited by CPTcAMP or dexamethasone (DEX), supporting the proapoptotic role of NFkB on TCR-induced apoptosis. Anti-CD3 not only increases kB- but diminishes GC response element (GRE)-activity induced by DEX, suggesting that TCR-mediated blockade of GC-induced apoptosis involves not only the proposed antiapoptotic action of NF-kB on GC, but also the inhibition of GRE-regulated proapoptotic genes. To test the involvement of CRE-driven transcription in the cAMP dual apoptotic regulation, cells were transfected with a CRE decoy DNA oligomer. Blockade of CRE transactivation with decoy targeting of CRE completely blocked the protection of TCR-induced apoptosis by cAMP, while it did not modify the enhancement by cAMP on GC-induced apoptosis. We show that CRE-binding factors have a definite role in T-cell apoptosis: they are involved in cAMP protection of TCR- but not in cAMP potentiation of GC-induced apoptosis.

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