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

Abstract

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.

From ‘Understanding the Brain by Creating the Brain’ towards manipulative neuroscience

“…In the NO model (one-third on left-hand side of figure 5), which was first proposed by Kuroda et al (2001) and then extensively studied in combination with electrical properties of dendrites by Ogasawara et al (2007), NO activates soluble guanylyl cyclase (sGC), and the activated sGC catalyses the conversion of GTP into cGMP, which activates cGMP-dependent protein kinase (PKG). PKG phosphorylates its substrate, G-substrate and the phosphorylated G-substrate preferentially inhibits protein phosphatase 2A (PP2A).…”

Systems Biology Perspectives on Cerebellar Long-Term Depression

“…Ogasawara et al [30] hypothesized that NO was crucial in context-dependent selection of learning modules because neighboring PF activity, which reflects the context of behavior, determines local [NO]. They combined established simulation models of electrophysiology, calcium dynamics ( fig.…”

“…An animal experiment was suggested to verify their hypotheses. For the detailed procedures, refer to the original paper [30] .…”

“…Without such reversal mechanisms, LTD would eventually reach saturation, preventing the occurrence of further learning events. A presynaptically synthesized messenger nitric oxide (NO) is a crucial 'gatekeeper' [30] for cerebellar plasticity; LTD and LTP are induced only in the presence of NO, and its deprivation prevents both LTD and LTP [ 27, 31-36, reviewed in 7, 37 ]. The direction of gain change is [Ca 2+ ]-dependent, with a high threshold for LTD and a low threshold for LTP [25,29] .…”

“…To elucidate the key pathways of LTD and their computational roles in cerebellar learning, we have studied the systems biology of PF-PC synaptic plasticity and proposed the following hypotheses: (1) MAPK and PKC activate each other, generating a positive feedback loop, and because of this loop, phosphorylation of AMPARs is an all-or-none event [48] ; (2) the IP 3 receptor (IP 3 R) is capable of detecting conjunctive PF and CF inputs [49] , which is a necessary feature for cerebellar associative learning; (3) NO reflects the relevance of a given context and enables context-dependent selection of learning modules in the cerebellum [30] . In this article, we first review the theoretical studies on cerebellar LTD, mainly focusing on our own published work, followed by a discussion of the possible effects of stochasticity, localization, diffusion, and scaffolding on synaptic transmission and plasticity.…”