1: Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of LTD in Motor Learning.

Neuron

(2018) 99: 985-998, doi: 10.1016/j.neuron.2018.07.034.

Kakegawa W, Katoh A, Narumi S, Miura E, Motohashi J, Takahashi A, Kohda K, Fukazawa Y, Yuzaki M*, Matsuda S* (*: co-corresponding authors)

In recent years, it has been suggested that the physical basis of memory and learning is the increase or decrease in the number of AMPA-type glutamate receptors (AMPA receptors), which are responsible for synaptic transmission. For example, motor memory, which is learned through physical practice, has been thought to depend on the activity-dependent endocytosis of AMPA receptors in cerebellar synapses and the associated long-term depression (LTD) of synaptic transmission efficiency. However, recent reports of genetically modified mice lacking molecules involved in LTD that can still perform motor learning normally have raised the need to reconsider whether a causal relationship exists between memory and learning at the organismal level and LTD at the synaptic level. To answer this fundamental question, we have developed a new optogenetic tool (PhotonSABER) that can reversibly inhibit AMPA receptor endocytosis with light. Interestingly, in mice expressing PhotonSABER in the cerebellum, both LTD and motor memory were normal without light irradiation, whereas both were significantly impaired under light irradiation. This allowed us to directly prove that LTD in cerebellar synapses is a crucial event for motor memory and learning. This achievement is expected to provide valuable information for understanding the molecular basis of memory and learning.

(Wataru Kakegawa, Associate Professor, Department of Physiology, 76 equivalent)

Cell Stem Cell.

2018 Sep 6;23(3):382-395.e5. doi: 10.1016/j.stem.2018.07.001. Epub 2018 Aug 9.

Sadahiro T, Isomi M, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tamura F, Tani H, Tohyama S, Fujita J, Miyoshi H, Kawamura Y, Goshima N, Iwasaki YW, Murano K, Saito K, Oda M, Andersen P, Kwon C, Uosaki H, Nishizono H, Fukuda K, Ieda M

In recent years, regenerative medicine using cardiomyocytes differentiated from pluripotent stem cells (ES cells, iPS cells) has been gaining attention. The common method for inducing cardiomyocytes from pluripotent stem cells involves the sequential use of multiple soluble factors to induce cardiac mesoderm cells, the stem cells of the heart, which then differentiate into cardiomyocytes. However, this method has several challenges: 1) the induction process is complex, 2) the induction efficiency is unstable, and 3) the soluble factors are expensive. Furthermore, the molecular mechanisms of differentiation induction and the factors that induce cardiac mesoderm have not been identified. We hypothesized that by elucidating the molecular mechanisms and identifying the induction factors, it would be possible to selectively induce cardiac mesoderm cells from pluripotent stem cells using only gene expression. Through a screening based on direct reprogramming, we discovered the gene Tbx6, which directly induces cardiac mesoderm cells from fibroblasts. By introducing Tbx6 into mouse ES cells and human iPS cells, we succeeded in inducing cardiac mesoderm cells without using soluble factors. Furthermore, we found that by adjusting the duration of Tbx6 expression, it is also possible to induce skeletal muscle and cartilage cells, which also differentiate from the mesoderm. From these findings, we discovered that Tbx6 is a key factor controlling cardiac and mesodermal differentiation from pluripotent stem cells, and we further clarified its molecular mechanism. This research was featured on the cover of Cell Stem Cell (Figure 2).

(Masaki Ieda, Professor, Department of Cardiovascular Medicine, University of Tsukuba, 74th class; Takeru Sadahiro, Hospital Lecturer, Department of Cardiovascular Medicine, University of Tsukuba, 86th class)

Cytokine Growth Factor Rev.

2018 Aug;42:27-36. doi: 10.1016/j.cytogfr.2018.07.002.

Mikami Y, Takada Y, Hagihara Y, Kanai T