Mechanistic target of rapamycin is necessary for changes in dendritic spine morphology associated with long-term potentiation

1. Because induction of associative long-term potentiation (LTP) in the dentate gyrus is thought to depend on Ca2+ influx through channels controlled by N-methyl-D-aspartate (NMDA) receptors, quantitative modeling was performed of synaptically mediated Ca2+ influx as a function of synaptic coactivation. The goal was to determine whether Ca2+ influx through NMDA-receptor channels was, by itself, sufficient to explain associative LTP, including control experiments and the temporal requirements of LTP. 2. Ca2+ influx through NMDA-receptor channels was modeled at a synapse on a dendritic spine of a reconstructed hippocampal dentate granule cell when 1-115 synapses on spines at different dendritic locations were activated eight times at frequencies of 10-800 Hz. The resulting change in [Ca2+] in the spine head was estimated from the Ca2+ influx with the use of a model of a dendritic spine that included Ca2+ buffers, pumps, and diffusion. 3. To use a compelling model of synaptic activation, we developed quantitative descriptions of the NMDA and non-NMDA receptor-mediated conductances consistent with available experimental data. The experimental data reported for NMDA and non-NMDA receptor-channel properties and data from other non-LTP experiments that separated the NMDA and non-NMDA receptor-mediated components of synaptic events proved to be limiting for particular synaptic variables. Relative to the non-NMDA glutamate-type receptors, 1) the unbinding of transmitter from NMDA receptors had to be slow, 2) the transition from the bound NMDA receptor-transmitter complex to the open channel state had to be even slower, and 3) the average number of NMDA-receptor channels at a single activated synapse on a single spine head that were open and conducting at a given moment in time had to be very small (usually less than 1). 4. With the use of these quantitative synaptic conductance descriptions. Ca2+ influx through NMDA-receptor channels at a synapse was computed for a variety of conditions. For a constant number of pulses, Ca2+ influx was calculated as a function of input frequency and the number of coactivated synapses. When few synapses were coactivated, Ca2+ influx was small, even for high-frequency activation. However, with larger numbers of coactivated synapses, there was a steep increase in Ca2+ influx with increasing input frequency because of the voltage-dependent nature of the NMDA receptor-mediated conductance. Nevertheless, total Ca2+ influx was never increased more than fourfold by increasing input frequency or the number of coactivated synapses.(ABSTRACT TRUNCATED AT 400 WORDS)

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Impact of JNK and Its Substrates on Dendritic Spine Morphology

Cells ◽

10.3390/cells9020440 ◽

2020 ◽

Vol 9 (2) ◽

pp. 440 ◽

Cited By ~ 2

Author(s):

Emilia Komulainen ◽

Artemis Varidaki ◽

Natalia Kulesskaya ◽

Hasan Mohammad ◽

Christel Sourander ◽

...

Keyword(s):

Dendritic Spine ◽

Pyramidal Neurons ◽

Lucifer Yellow ◽

Dendrite Morphology ◽

Spine Morphology ◽

Kinase Substrate ◽

Basal Dendrites ◽

Dendritic Spine Morphology ◽

Mushroom Spines

The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory proteins. JNK1 also phosphorylates dendritic spine proteins, and Jnk1-/- mice display a long-term depression deficit. Whether JNK1 or other JNKs regulate spine morphology is thus of interest. Here, we characterize dendritic spine morphology in hippocampus of mice lacking Jnk1-/- using Lucifer yellow labelling. We find that mushroom spines decrease and thin spines increase in apical dendrites of CA3 pyramidal neurons with no spine changes in basal dendrites or in CA1. Consistent with this spine deficit, Jnk1-/- mice display impaired acquisition learning in the Morris water maze. In hippocampal cultures, we show that cytosolic but not nuclear JNK, regulates spine morphology and expression of phosphomimicry variants of JNK substrates doublecortin (DCX) or myristoylated alanine-rich C kinase substrate-like protein-1 (MARCKSL1), rescue mushroom, thin, and stubby spines differentially. These data suggest that physiologically active JNK controls the equilibrium between mushroom, thin, and stubby spines via phosphorylation of distinct substrates.

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Bistable MAP kinase activity: a plausible mechanism contributing to maintenance of late long-term potentiation

AJP Cell Physiology ◽

10.1152/ajpcell.00447.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. C503-C515 ◽

Cited By ~ 25

Author(s):

Paul Smolen ◽

Douglas A. Baxter ◽

John H. Byrne

Keyword(s):

Map Kinase ◽

Dendritic Spine ◽

Mapk Pathway ◽

Long Term Potentiation ◽

Long Term Memory ◽

Stable States ◽

Mapk Activity ◽

Stochastic Fluctuations ◽

Term Potentiation

Bistability of MAP kinase (MAPK) activity has been suggested to contribute to several cellular processes, including differentiation and long-term synaptic potentiation. A recent model (Markevich NI, Hoek JB, Kholodenko BN. J Cell Biol 164: 353–359, 2004) predicts bistability due to interactions of the kinases and phosphatases in the MAPK pathway, without feedback from MAPK to earlier reactions. Using this model and enzyme concentrations appropriate for neurons, we simulated bistable MAPK activity, but bistability was present only within a relatively narrow range of activity of Raf, the first pathway kinase. Stochastic fluctuations in molecule numbers eliminated bistability for small molecule numbers, such as are expected in the volume of a dendritic spine. However, positive-feedback loops have been posited from MAPK up to Raf activation. One proposed loop in which MAPK directly activates Raf was incorporated into the model. We found that such feedback greatly enhanced the robustness of both stable states of MAPK activity to stochastic fluctuations and to parameter variations. Bistability was robust for molecule numbers plausible for a dendritic spine volume. The upper state of MAPK activity was resistant to inhibition of MEK activation for >1 h, which suggests that inhibitor experiments have not sufficed to rule out a role for persistent MAPK activity in the maintenance of long-term potentiation (LTP). These simulations suggest that persistent MAPK activity and consequent upregulation of translation may contribute to LTP maintenance and to long-term memory. Experiments using a fluorescent MAPK substrate may further test this hypothesis.

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