Nuclear Translocation of Jacob in Hippocampal Neurons after Stimuli Inducing Long-Term Potentiation but Not Long-Term Depression

Abstract

BackgroundIn recent years a number of potential synapto-nuclear protein messengers have been characterized that are thought to be involved in plasticity-related gene expression, and that have the capacity of importin- mediated and activity-dependent nuclear import. However, there is a surprising paucity of data showing the nuclear import of such proteins in cellular models of learning and memory. Only recently it was found that the transcription factor cyclic AMP response element binding protein 2 (CREB2) transits to the nucleus during long-term depression (LTD), but not during long-term potentiation (LTP) of synaptic transmission in hippocampal primary neurons. Jacob is another messenger that couples NMDA-receptor-activity to nuclear gene expression. We therefore aimed to study whether Jacob accumulates in the nucleus in physiological relevant models of activity-dependent synaptic plasticity.Methodology/Principal FindingsWe have analyzed the dynamics of Jacob's nuclear import following induction of NMDA-receptor dependent LTP or LTD at Schaffer collateral-CA1 synapses in rat hippocampal slices. Using time-lapse imaging of neurons expressing a Jacob-Green-Fluorescent-Protein we found that Jacob rapidly translocates from dendrites to the nucleus already during the tetanization period of LTP, but not after induction of LTD. Immunocytochemical stainings confirmed the nuclear accumulation of endogenous Jacob in comparison to apical dendrites after induction of LTP but not LTD. Complementary findings were obtained after induction of NMDA-receptor dependent chemical LTP and LTD in hippocampal primary neurons. However, in accordance with previous studies, high concentrations of NMDA and glycine as well as specific activation of extrasynaptic NMDA-receptors resembling pathological conditions induce an even more profound increase of nuclear Jacob levels.Conclusions/SignificanceTaken together, these findings suggest that the two major forms of NMDA-receptor dependent synaptic plasticity, LTP and LTD, elicit the transition of different synapto-nuclear messengers albeit in both cases importin-mediated retrograde transport and NMDA-receptor activation is required.

Importin-7 mediates memory consolidation through regulation of nuclear translocation of training-activated MAPK in Drosophila

“…Importins are known to be involved in longterm synaptic plasticity in both invertebrates and vertebrates (18,(40)(41)(42)(43)(44). The current work confirms that DIM-7 is indeed critical at the behavioral level in mediating LTM consolidation.…”

Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-d-aspartate (NMDA) Receptors

“…The ECS contained 150 mM NaCl, 2 mM CaCl 2 , 5 mM KCl, 10 mM HEPES, 30 mM glucose, 50 M forskolin, 0.1 M rolipram, and 50 M picrotoxin, pH 7.4. The chemical long term depression (LTD) protocol followed that of a previous study (27). Cortical cultures (14 -16 DIV) were incubated with prewarmed extracellular solution (ECS: 150 mM NaCl, 2 mM CaCl 2 , 5 mM KCl, 10 mM HEPES, 33 mM glucose, 0.5 M tetrodotoxin, pH 7.4) for 10 min, then 20 M NMDA and 20 M glycine were added for the indicated times.…”

Macromolecular transport in synapse to nucleus communication

“…An importin a is required for CREB2 transport from distal dendrites to the soma in both rodent hippocampal and Aplysia sensorimotor synapses [81]. Interestingly, testing of Jacob under similar NMDAR stimulation paradigms in hippocampal neurons revealed importin-dependent nuclear accumulation under LTP, but not LTD [82]. CRTC1 (also known as TORC) is another CREB pathway modulator recently reported to translocate from synapse to nucleus [55].…”