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Séminaire impromptu - Haruhiko BitoIlluminating activity-dependent signaling and circuits

Abstract :

Haruhiko Bito (Université de Tokyo)

Deciphering the intricate and interactive relationship between the information encoded in the genome and the ongoing synaptic activity is critical for understanding the molecular and cellular signaling underlying long-term memory formation and maintenance of long-lasting changes within the brain.

To systematically dissect this question, we investigated the molecular basis of the signaling from synapses to the nucleus and from the nucleus to the synapses, which crucially determines the persistence of synaptic plasticity. We thus uncovered an activity-dependent protein kinase cascade CaMKK-CaMKIV that critically controls the amplitude and time course of phosphorylation of a nuclear transcription factor CREB downstream of synaptic activity, thereby activating a plethora of adaptive transcriptional responses within an active neuronal circuit.

 We also identified a novel “inverse” synaptic tagging mechanism in which one of CREB’s target gene, Arc, acts a brake that helps weaken the non-potentiated synapses during the maintenance phase of synaptic plasticity. In genomic parlance, Arc’s rapid induction following strong physiological stimuli is dictated by a potent synaptic activity-responsive element (SARE) present in its enhancer/promoter region, which strikingly harbors a unique cluster of binding sites for CREB, MEF2 and SRF/TCF.

Based on this discovery, we created a synthetic promoter E-SARE which now allows to map, label, record and manipulate active neuronal ensembles in various areas of the brain in vivo. Recently, we designed a new set of genetically encoded Ca2+ indicators (GECIs), such as R-CaMP2, which are molecular spies of neuronal activity with most desirable properties such as fast speed and signal linearity. This was largely achieved by exchanging the M13 sequence of classical GECIs with the sensitive CaM-binding sequence of neuronal CaMKK. These efforts collectively start to illuminate key molecular and cellular events that are essential in neuronal coding and information processing in active neuronal circuits and systems in vivo. 

Selected publications

Inoue M, Takeuchi A, Horigane S, Ohkura M, Gengyo-Ando K, Fujii H, Kamijo S, Takemoto-Kimura S, Kano M, Nakai J, Kitamura K, Bito H. Rational design of a high-affinity, fast, red calcium indicator R-CaMP2. Nature Methods. 12, 64-70, 2015.

Nonaka M, Kim R, Fukushima H, Sasaki K, Suzuki K, Okamura M, Ishii Y, Kawashima T, Kamijo S, Takemoto-Kimura S, Okuno H, Kida S, Bito H. Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory. Neuron, 84: 92-106, 2014.

Vousden DA, Epp J, Okuno H, Nieman BJ, van Eede M, Dazai J, Ragan T, Bito H, Frankland PW, Lerch JP, Henkelman RM. Whole-brain mapping of behaviourally induced neural activation in mice. Brain Struct Funct., in press. Kawashima T, Okuno H, Bito H. A new era for functional labeling of neurons: activity-dependent promoters have come of age. Front Neural Circuits. 8: 37, 2014.

Nonaka M, Fujii H, Kim R, Kawashima T, Okuno H, Bito H. Untangling the two-way signaling route from synapses to the nucleus, and from the nucleus back to the synapses. Phil. Trans. Roy Soc B Biol. Sci, 369(1633): 20130150, 2014.

Ageta-Ishihara N, Miyata T, Ohshima C, Watanabe M, Sato Y, Hamamura Y, Higashiyama T, Mazitschek R, Bito H, Kinoshita M. Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation. Nature Communications, 4: 2532, 2013.

Kawashima T, Kitamura K, Suzuki K, Nonaka M, Kamijo S, Takemoto-Kimura S, Kano M, Okuno H, Ohki K, Bito H. Functional labeling of neuronal ensemble and axonal projections in vivo using a synthetic activity-dependent promoter E-SARE. Nature Methods, 10: 889–895, 2013.

Mikuni T, Uesaka N, Okuno H, Hirai H, Deisseroth K, Bito H, Kano M. The immediate early gene Arc/Arg3.1 is a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum. Neuron 78, 1024-1035, 2013.

Scientific focus :

My laboratory’s primary goal is to elucidate the basic signal transduction mechanisms which mediate key processes underlying various brain functions, such as learning, memory or emotion. Our central nervous system is physically wired and organized based on evolutionary and developmental principles that are primarily encoded into the genome and that are highly conserved in mammals from rodents to primates. This neural network, however, is able to recognize and memorize external and internal events as they occur. And furthermore, the brain stands out by its intrinsic capacity to extract patterns and rules from these events, and to consciously associate them with abstract meaning and affective valence, while also unconsciously facilitating coordinated body responses. Neurochemistry has recently become a field of excitement where we are now able to measure changes in cellular messengers or modifications in signaling molecules in critical parts of the neurons such as the dendritic spines or the axon terminals, as the neurons summate synaptic potentials or fire action potentials.

What are the precise nature and the whole spectrum of the molecular changes in the neurons that undergo heavy or patterned electrical activity? What are the molecular rules that govern these local and global changes, both electrical and chemical? How are these events, in turn, converted into more profound modifications of the synaptic wiring mechanisms? And finally do these alterations genuinely underlie certain kinds of information processing and storage?

To address these issues, my laboratory currently focuses its resources into three basic aims:

1) Deciphering the signaling from synapses to the nucleus, and back from the nucleus to the synapses during learning and memory.

2) Dissecting the role of Ca2+-dependent signaling during circuit formation in the perinatal brain.

3) Developing novel gene-encoded probes and tools for elucidating neuronal circuit dynamics through hierarchical imaging and manipulation of ensembles of active synapses, neurons and engrams.  

Christophe Mulle / Research Director CNRS UMR 5297 Interdisciplinary Institute of Neuroscience University of Bordeaux christophe.mulle(at)