Biomedical subjects

I M Mansuy

Publications and source records attributed to I M Mansuy.

14 recordsLinked to original sources

PubMed2007

Calcineurin (protein phosphatase 2B) is involved in the mechanisms of action of antidepressants.

Calcineurin (PP2B) is a Ca(2+)-dependent protein phosphatase enriched in the brain that takes part in intracellular signaling pathways regulating synaptic plasticity and neuronal functions. Calcineurin-dependent pathways are important for complex brain functions such as learning and memory. More recently, they have been suggested to play a role in the processing of emotional information. The aim of this study was to investigate whether calcineurin may be involved in the effect of antidepressants. We first found that chronic antidepressant treatment in mice leads to an increase of calcineurin levels in the hippocampus. We then studied the behavioral and molecular responses to fluoxetine of mice with a genetic overactivation of calcineurin in the hippocampus (constitutively-activated calcineurin transgenic mouse line #98, CN98 mice). We observed that CN98 mice are more sensitive to the behavioral effect of fluoxetine and desipramine tested in the tail suspension test. Moreover, the basal expression of growth factor brain-derived neurotrophic factor and subunit 1 of AMPA glutamate receptor, GluR1, both of which are modified after chronic antidepressant administration, are altered in the hippocampus of CN98 mice. These results suggest that calcineurin-dependent dephosphorylation plays an important role in the mechanisms of action of antidepressants, providing a new starting point for developing improved therapeutic treatments for depression.

Animals↗

PubMed2007

Conditional transgenesis and recombination to study the molecular mechanisms of brain plasticity and memory.

In the postgenomic era, a primary focus of mouse genetics is to elucidate the role of individual genes in vivo. However, in the nervous system, studying the contribution of specific genes to brain functions is difficult because the brain is a highly complex organ with multiple neuroanatomical structures, orchestrating virtually every function in the body. Further, higher-order brain functions such as learning and memory simultaneously recruit several signaling cascades in different subcellular compartments and have highly fine-tuned spatial and temporal components. Conditional transgenic and gene targeting methodologies, however, now offer valuable tools with improved spatial and temporal resolution for appropriate studies of these functions. This chapter provides an overview of these tools and describes how they have helped gain better understanding of the role of candidate genes such as the NMDA receptor, the protein kinase CaMKIIIalpha, the protein phosphatases calcineurin and PP1, or the transcription factor CREB, in the processes of learning and memory. This review illustrates the broad and innovative applicability of these methodologies to the study of brain plasticity and cognitive functions.

Animals↗

PubMed2005

Protein phosphatases and their potential implications in neuroprotective processes.

Several neurological disorders such as stroke, amyotrophic lateral sclerosis and epilepsy result from excitotoxic events and are accompanied by neuronal cell death. These processes engage multiple signalling pathways and recruit numerous molecular components, in particular several families of protein kinases and protein phosphatases. While many investigations have examined the importance of protein kinases in excitotoxicity, protein phosphatases have not been well studied in this context. However, recent advances in understanding the functions of protein phosphatases have suggested that they may play a neuroprotective role. In this review, we summarize some of the recent findings that illustrate the pleiotropic and complex functions of tyrosine and serine/threonine protein phosphatases in the cascade of events leading to neuronal cell death, and highlight their potential intervention in limiting the extent of neuronal death.

Animals↗

PubMed2001

Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin.

The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, we examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent rtTA system to express a calcineurin inhibitor reversibly in the mouse brain, we find that the transient reduction of calcineurin activity facilitates LTP in vitro and in vivo. This facilitation is PKA dependent and persists over several days in vivo. It is accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements are reversed fully by suppression of transgene expression. These results demonstrate that endogenous calcineurin constrains LTP and memory.

Animals↗

PubMed2000

Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP.

Coincident pre- and postsynaptic activity generates long-term potentiation (LTP), a possible cellular model of learning and memory. LTP has two components: (1) an increase in the excitatory postsynaptic potential (EPSP), and (2) an increase in the ability of the EPSP to generate a spike (E-S coupling of LTP). We have used pharmacological and genetic approaches to address the molecular nature of E-S coupling in CA1 pyramidal neurons. Blockade of the Ca2+-sensitive phosphatase, calcineurin, prevents induction of E-S coupling without interfering with LTP of the EPSP. Calcineurin produces its effect on E-S coupling by inducing a long-lasting depression (LTD) of the GABA(A)-mediated inhibitory postsynaptic potentials (IPSPs). This LTD of the IPSP was prevented by blockade of NMDA receptors. Thus, the tetanus that elicits NMDA-dependent LTP mediates a coordinately regulated double function. It produces LTP of the EPSP and, concomitantly, LTD of the IPSP that leads to enhancement of E-S coupling.

Animals↗

PubMed2000

Tetracycline-regulated gene expression in the brain.

The possibility of regulating individual gene activities in the mouse brain via the tetracycline-controlled transcriptional activation systems has sparked the development of novel mouse models aimed at elucidating the molecular mechanisms of brain disorders such as Huntington's, prion and Parkinson's diseases. In the past year, novel experimental strategies and methodological advances have emerged, contributing to the resolution of some of the initial limitations of these regulatory systems.

Animals↗

PubMed2000

Mouse genetics in cell biology.

Genetic methodologies have provided powerful means for investigating the cellular and molecular mechanisms of biological functions. Cell-cell and cell-extracellular matrix interactions in particular have been studied in different functional systems with genetically modified animals. In the peripheral and central nervous system, many aspects of specific processes based on such interactions, including myelination, synaptic transmission and plasticity, have been elucidated at the cellular and molecular level. Importantly, genetic approaches have greatly advanced the understanding of pathologies resulting from impaired cellular interactions in the brain and the periphery. In this review, some of the most relevant genetic mouse models in cell biology and the methodologies employed for their production will be described. In addition their usefulness for studies of the mechanisms of hereditary neuropathies, learning and memory, and tumorigenesis will be illustrated.

Animals↗

PubMed1998

Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin.

To investigate the role of phosphatases in synaptic plasticity using genetic approaches, we generated transgenic mice that overexpress a truncated form of calcineurin under the control of the CaMKIIalpha promoter. Mice expressing this transgene show increased calcium-dependent phosphatase activity in the hippocampus. Physiological studies of these mice and parallel pharmacological experiments in wild-type mice reveal a novel, intermediate phase of LTP (I-LTP) in the CA1 region of the hippocampus. This intermediate phase differs from E-LTP by requiring multiple trains for induction and in being dependent on PKA. It differs from L-LTP in not requiring new protein synthesis. These data suggest that calcineurin acts as an inhibitory constraint on I-LTP that is relieved by PKA. This inhibitory constraint acts as a gate to regulate the synaptic induction of L-LTP.

Action Potentials↗

PubMed1998

Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory.

To investigate the roles phosphatases play in hippocampal-dependent memory, we studied transgenic mice overexpressing a truncated form of calcineurin. These mice have normal short-term memory but defective long-term memory evident on both a spatial task and on a visual recognition task, providing genetic evidence for the role of the rodent hippocampus in spatial and nonspatial memory. The defect in long-term memory could be fully rescued by increasing the number of training trials, suggesting that the mice have the capacity for long-term memory. We next analyzed mice overexpressing calcineurin in a regulated manner and found the memory defect is reversible and not due to a developmental abnormality. Our behavioral results suggest that calcineurin has a role in the transition from short- to long-term memory, which correlates with a novel intermediate phase of LTP.

Animals↗

PubMed1998

Inducible and reversible gene expression with the rtTA system for the study of memory.

To obtain rapidly inducible and reversible expression of transgenes in the forebrain of the mouse, we have combined the reverse tetracycline-controlled transactivator (rtTA) system with the CaMKIIalpha promoter. We show that doxycycline induces maximal gene expression in neurons of the forebrain within 6 days and that this expression can be reversed by removal of doxycycline. Using calcineurin as a test transgene, we show that doxycycline-induced expression impairs both an intermediate form of LTP (I-LTP) in the hippocampus and the storage of spatial memory. The reversibility of the rtTA system in turn allowed us to examine the effects of the transgene on memory retrieval after normal storage had occurred. This examination suggests that retrieval requires some of the same molecular components required for storage.

Animals↗

PubMed1997

Memory and behavior: a second generation of genetically modified mice.

The use of standard genetic techniques, such as gene targeting and transgenesis, to study cognitive function in adult animals suffers from the limitations that the gene under study is often altered in many brain regions, and that this alteration is present during the entire developmental history of the animal. Furthermore, to relate cognitive defects to neuronal mechanisms of memory, studies have relied on examining long-term potentiation - an artificially induced form of synaptic plasticity. Recent technical advances allow the expression of a genetic alteration in mice to be restricted both anatomically and temporally, making possible a more precise examination of the role of various forms of synaptic plasticity, such as long-term potentiation and long-term depression, in memory formation. Recordings from so-called 'place cells' -hippocampal cells that encode spatial location -in freely moving, genetically modified mice have further advanced our understanding of how the actual cellular representation of space is influenced by genetic alterations that affect long-term potentiation.

Animals↗

PubMed1997

Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation.

Protease nexin-1 (PN-1), a member of the serpin superfamily, controls the activity of extracellular serine proteases and is expressed in the brain. Mutant mice overexpressing PN-1 in brain under the control of the Thy-1 promoter (Thy 1/PN-1) or lacking PN-1 (PN-1-/-) were found to develop epileptic activity in vivo and in vitro. Theta burst-induced long-term potentiation (LTP) and NMDA receptor-mediated synaptic transmission in the CA1 field of hippocampal slices were augmented in Thy 1/PN-1 mice and reduced in PN-1-/- mice. Compensatory changes in GABA-mediated inhibition in Thy 1/PN-1 mice suggest that altered brain PN-1 levels lead to an imbalance between excitatory and inhibitory synaptic transmission.

Amyloid beta-Protein Precursor↗

PubMed1997

Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene.

To examine the physiological role of the Fyn tyrosine kinase in neurons, we generated transgenic mice that expressed a fyn cDNA under the control of the calcium/calmodulin-dependent protein kinase IIalpha promoter. With this promoter, we detected only low expression of Fyn in the neonatal brain. In contrast, there was strong expression of the fyn-transgene in neurons of the adult forebrain. To determine whether the impairment of long-term potentiation (LTP) observed in adult fyn-deficient mice was caused directly by the lack of Fyn in adult hippocampal neurons or indirectly by an impairment in neuronal development, we generated fyn-rescue mice by introducing the wild-type fyn-transgene into mice carrying a targeted deletion in the endogenous fyn gene. In fyn-rescue mice, Schaffer collateral LTP was restored, even though the morphological abnormalities characteristic of fyn-deficient mice were still present. These results suggest that Fyn contributes, at least in part, to the molecular mechanisms of LTP induction.

Age Factors↗

PubMed1993

Variable and multiple expression of Protease Nexin-1 during mouse organogenesis and nervous system development.

Protease Nexin-1 (PN-1) also known as Glia-Derived Nexin (GDN) inhibits the activity of several serine proteases including thrombin, tissue (tPA)- and urokinase (uPA)-type plasminogen activators. These and other serine proteases seem to play roles in development and tissue homeostasis. To gain insight into where and when PN-1 might counteract serine protease activities in vivo, we examined its mRNA and protein expression in the mouse embryo, postnatal developing nervous system and adult tissues. These analyses revealed distinct temporal and spatial PN-1 expression patterns in developing cartilage, lung, skin, urogenital tract, and central and peripheral nervous system. In the embryonic spinal cord, PN-1 expression occurs in cells lining the neural canal that are different from the cells previously shown to express tPA. In the developing postnatal brain, PN-1 expression appears transiently in many neuronal cell populations. These findings suggest a role for PN-1 in the maturation of the central nervous system, a phase that is accompanied by the appearance of different forms of PN-1. In adults, few distinct neuronal cell populations like pyramidal cells of the layer V in the neocortex retained detectable levels of PN-1 expression. Also, mRNA and protein levels did not correspond in adult spleen and muscle tissues. The widespread and complex regulation of PN-1 expression during embryonic development and, in particular, in the early postnatal nervous system as well as in adult tissues suggests multiple roles for this serine protease inhibitor in organogenesis and tissue homeostasis.

Amyloid beta-Protein Precursor↗