Restricted and Regulated Overexpression Reveals Calcineurin as a Key Component in the Transition from Short-Term to Long-Term Memory

Mansuy, Isabelle M.; Mayford, Mark; Jacob, Betsy; Kandel, Eric R.; Bach, Mary Elizabeth

doi:10.1016/s0092-8674(00)80897-1

Cited by 335 publications

(194 citation statements)

References 46 publications

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“…PP2B/calcineurin has been reported to be important for mechanisms of synaptic plasticity such as long-term depression (LTD) (Mulkey et al, 1993;O'Dell and Kandel, 1994) and depotentiation (Zhuo et al, 1999). Furthermore, PP2B/ calcineurin has been shown to alter long-term potentiation (LTP) (Malleret et al, 2001;Winder et al, 1998;Mansuy et al, 1998). Thus, understanding mechanisms of PP2B/ calcineurin regulation could provide valuable insight into regulation of glutamatergic signal transduction.…”

Section: Discussionmentioning

confidence: 99%

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

Alagarsamy¹,

Saugstad²,

Warren

et al. 2005

Neuropharmacology

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Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.

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Section: Discussionmentioning

confidence: 99%

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

Alagarsamy¹,

Saugstad²,

Warren

et al. 2005

Neuropharmacology

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“…We next explored whether the CaN-A-GABA A receptor complex formation is sufficient for the induction of LTD. We expressed the CaN catalytic domain, CaN-A␣, in the hippocampus of transgenic mice (CN98 mutant mice) (Mansuy et al, 1998;Winder et al, 1998). We affinity precipitated extracts from the CN98 mutant and control CA1 slices using GST-␣ 1 334 -420 , -␤ 2 327-451 , and -␥ 2S 317-442 .…”

Section: Overexpression Of Can-a Reduces Mgaba a R-ipscsmentioning

confidence: 99%

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

et al. 2003

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Long-term depression (LTD) is an activity-dependent weakening of synaptic efficacy at individual inhibitory synapses, a possible cellular model of learning and memory. Here, we show that the induction of LTD of inhibitory transmission recruits activated calcineurin (CaN) to dephosphorylate type-A GABA receptor (GABAARs) via the direct binding of CaN catalytic domain to the second intracellular domain of the GABAAR-γ2subunits. Prevention of the CaN–GABAAreceptor complex formation by expression of an autoinhibitory domain of CaN in the hippocampus of transgenic mice blocks the induction of LTD. Conversely, genetic expression of the CaN catalytic domain in the hippocampus depresses inhibitory synaptic responses, occluding LTD. Thus, an activity-dependent physical and functional interaction between CaN and GABAAreceptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses.

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“…Behavioral experiments carried out in the laboratory of Eric Kandel demonstrated that long-term memory is lost after expression of a truncated dominant negative form of calcineurin in the hippocampus of trained mice. However, the ability to precisely remember the previously learned tasks can be completely restored after extinction of the dominant negative calcineurin (89). Readers interested in exploring further applications using second-generation mouse models in physiology are referred to several additional but more specialized reviews for cardiovascular disease (112), for neurobiology (88,159), for endocrinology/metabolism (117), and for cancer (60,63).…”

Section: Invited Reviewmentioning

confidence: 99%

Of mice and models: improved animal models for biomedical research

Bockamp

Maringer

Spangenberg

et al. 2002

Physiological Genomics

147

109

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The ability to engineer the mouse genome has profoundly transformed biomedical research. During the last decade, conventional transgenic and gene knockout technologies have become invaluable experimental tools for modeling genetic disorders, assigning functions to genes, evaluating drugs and toxins, and by and large helping to answer fundamental questions in basic and applied research. In addition, the growing demand for more sophisticated murine models has also become increasingly evident. Good state-of-principle knowledge about the enormous potential of second-generation conditional mouse technology will be beneficial for any researcher interested in using these experimental tools. In this review we will focus on practice, pivotal principles, and progress in the rapidly expanding area of conditional mouse technology. The review will also present an internet compilation of available tetracycline-inducible mouse models as tools for biomedical research ( http://www.zmg.uni-mainz.de/tetmouse/ ).

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Restricted and Regulated Overexpression Reveals Calcineurin as a Key Component in the Transition from Short-Term to Long-Term Memory

Cited by 335 publications

References 46 publications

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Of mice and models: improved animal models for biomedical research

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Restricted and Regulated Overexpression Reveals Calcineurin as a Key Component in the Transition from Short-Term to Long-Term Memory

Cited by 335 publications

References 46 publications

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

Interaction of Calcineurin and Type-A GABA Receptor γ2Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Of mice and models: improved animal models for biomedical research

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Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses