Nitric Oxide Regulates Input Specificity of Long-Term Depression and Context Dependence of Cerebellar Learning

Recent studies have shown that multiple internal models are acquired in the cerebellum and that these can be switched under a given context of behavior. It has been proposed that long-term depression (LTD) of parallel fiber (PF)–Purkinje cell (PC) synapses forms the cellular basis of cerebellar learning, and that the presynaptically synthesized messenger nitric oxide (NO) is a crucial “gatekeeper” for LTD. Because NO diffuses freely to neighboring synapses, this volume learning is not input-specific and brings into question the biological significance of LTD as the basic mechanism for efficient supervised learning. To better characterize the role of NO in cerebellar learning, we simulated the sequence of electrophysiological and biochemical events in PF–PC LTD by combining established simulation models of the electrophysiology, calcium dynamics, and signaling pathways of the PC. The results demonstrate that the local NO concentration is critical for induction of LTD and for its input specificity. Pre- and postsynaptic coincident firing is not sufficient for a PF–PC synapse to undergo LTD, and LTD is induced only when a sufficient amount of NO is provided by activation of the surrounding PFs. On the other hand, above-adequate levels of activity in nearby PFs cause accumulation of NO, which also allows LTD in neighboring synapses that were not directly stimulated, ruining input specificity. These findings lead us to propose the hypothesis that NO represents the relevance of a given context and enables context-dependent selection of internal models to be updated. We also predict sparse PF activity in vivo because, otherwise, input specificity would be lost

A Kinetic Model of Dopamine- and Calcium-Dependent Striatal Synaptic Plasticity

Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction

ショウノウ ガクシュウ デ ニュウリョク タイミング オ ケンシュツ スル ジコ サイセイテキ Ca2+ シグナル ノ シミュレーション

http://library.naist.jp/mylimedio/dllimedio/show.cgi?bookid=100038242&oldid=70124修士 (Master)理学 (Science)修第2207

Overview of the Model

<div><p>(A) The electrophysiological structure of the model. Spine necks connect spine heads (arrowhead) to an unbranched dendrite. The right-hand end of the dendrite corresponds to the soma, which is voltage-clamped. Vertical lines indicate compartmentalization of the dendrite.</p><p>(B) Block diagram of signaling pathways for calcium mobilization in each spine. Thick arrows and thin arrows indicate mobilization of calcium and activation of targets, respectively.</p><p>(C) Block diagram of AMPAR phosphorylation. Raf is a kinase that phosphorylates and activates MEK. Gq protein is a heterotrimeric guanine nucleotide binding protein that activates PLC. AA, arachidonic acid; DAG, diacylglycerol; PIP2, phosphatidylinositol bisphosphate; PKG, cGMP-dependent protein kinase; PLC, phospholipase C; PP2A, protein phosphatase 2A; sGC, soluble guanylyl cyclase.</p></div

Prediction of PF Activity In Vivo

<div><p>The spatial distribution of the PFs responsible for a certain movement in a certain context was assumed to follow a Gaussian distribution with a standard deviation of <i>σ</i>.</p><p>(A) The occurrence of the PFs responsible for a particular motion in a particular context was assumed to follow a Gaussian distribution, . <i>σ</i> is either 10 μm (solid line), 30 μm (dashed line), or 90 μm (dotted line). </p><p>(B) The probability-weighed time-averaged NO concentration, , is plotted against R. <i>σ</i> is either 10 μm (solid line), 30 μm (dashed line), or 90 μm (dotted line). </p><p>(C) Against <i>σ,</i> this panel plots the n at which [P-AMPAR]_50%,19min of AMPARs in a stimulated synapse (solid line) or in a neighboring unstimulated synapse (dashed line) was phosphorylated at 19 min.</p><p>(D) R_90%, which satisfies , is plotted against <i>σ</i>. </p><p>(E) n_90% (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0020179#s2" target="_blank">Results</a> for explanation) is plotted against <i>σ</i>. Solid line, stimulated synapse; dashed line, neighboring unstimulated synapse.</p><p>(F) The ratio of n_90% to the total number of the PFs projecting within R_90% μm of the dendritic plate is plotted against <i>σ</i>. Solid line, stimulated synapse; dashed line, neighboring unstimulated synapse.</p></div

Importance of the Time-Averaged Concentration of NO

<div><p>(A) Time course of AMPAR phosphorylation induced by continuous exposure to NO (red dotted line) or by NO pulses (blue solid line) equivalent in time-averaged concentrations (0.23 nM, 0.69 nM, and 1.1 nM from bottom to top).</p><p>(B) [P-AMPAR] at 19 min is plotted against the frequencies of NO pulses whose 1-s–averaged concentration was 0.23 nM, 0.69 nM, or 1.1 nM (from bottom to top).</p></div