Major Publications

Postsynaptic dynamics

1.  Sawada,T., Iino, Y., Yoshida, Y., Okazaki, H., Nomura, S., Shimizu, C., Arima, T., Juichi, T., Zhou, S.,  Sakurai, T., Yagishita, S., Yanagisawa, M., Toyoizumi, T., Kasai, H.*, Shi, S.* (2024) Prefrontal synaptic regulation of homeostatic sleep pressure revealed through synaptic chemogenetics. Science 385, 1459-1455. DOI: 10.1126/science.adl3043

To our surprise, sleep was induced when dendritic spines in the pyramidal cells of the mPFC were globally enlarged. This mechanism forms the basis of sleep homeostasis and highlights the critical role that spine structures play in cortical function.

2.  Ucar, H., Morimoto, Y., Watanabe, S., Noguchi, J., Iino, Y., Yagishita, S., Takahashi, N. & Kasai, H. (2021). Mechanical actions of dendritic-spine enlargement on presynaptic exocytosis. Nature 600: 686-689 (Dec 23).      F1000 Recommendation

Dendritic-spine enlargement pushed the presynaptic terminal, and strengthened the evoked glutamate release. The force of the enlargement was estimated as 0.5 kg.cm2 (similar to smooth muscle contraction!).This force must be used, first to cause long-term enlargement of spine, and, second to rapid enhance presynaptic functions. Since the effects last for 20 min, it may act as working memory. The mechanical actions must also benefit the understanding of ultrafast exocytosis.

3. Kasai, H, Ziv, N., Yagishita, S., Okazaki, H., Toyoizumi, T. (2021) Spine dynamics in the brain, mental disorders and artificial neural networks. Nature Reviews Neuroscience 22:407-422.

Our most recent review on the dendritic spines, consisting the algorithms of the brain. Spines show intrinsic dynamics in addition to activity-dependent plasticity (extrinsic dynamics).

4.  Iino, Y., Sawada, T., Yamaguchi, Tajiri, M., K., Ishii, S.,Kasai, H..* & Yagishita, S.* (2020) Dopamine D2 receptors in discrimination learning and spine enlargement. Nature 579: 555-560.   URL

Discovery of a relationship between the D2 dopamine receptor and pyschotic symptoms. D2R converted a dopamine dip into elevation of cytosolic cAMP and spine enlargement for discrimination learning in the nucleus accumbens.      Note: Dopamine D2 receptor in discrimination learning and psychosis        F1000 Recommendations

5. Noguchi, J., Nagaoka, A. , Hayama, T. , Ucar, H., Yagishita, S., Takahashi, N. & Kasai, H.. (2019). Bidirectional in vivo structural dendritic spine plasticity revealed by two-photon glutamate uncaging in the mouse neocortex. Scientific Reports, 9:13922. URL

 The first demonstration of spine enlargement and shrinkage by in vivo two-photon uncaging. Only a fraction of spine displayed the enlargement, while most showed the shrinkage which spreads laterally.

6. Humble, J., Hiratsuka, K., Kasai, H. & Toyoizumi, T. (2019). Intrinsic spine dynamics are critical for recurrent network learning in models with and without autism spectrum disorder. Frontiers in Computational Neuroscience 13,A38 .  

Spine fluctuations prevent run-away plasticity of Hebbian learning. Forgetting can be prevented by spontaneous firing. Excess fluctuations in ASD result in abnormal connectivities.    

7. Moda-Sava, R.N., Murdock, M.H., Parekh, P.K., Fetcho, R.N., Huang, B.S., Huynh, T.H., Witztum, J., Shaver, D.C., Rosenthal, D.L., Always, E.J., Lopez, K., Meng, Y., Nellissen, L., Grosenick, L., Deisseroth, K., Bito, H., Kasai, H. & Liston, C. (2019). Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced postsynaptic spine formation. Science, 364: eaat8078.  

Spine generation in PFC was obliterated in mice model of depression, and anti-depressant drug, ketamine, restored the generation. Our AS probe indicated the spine generation play key role in the long-term antidepressant effects of kitamine.      F1000 Recommendations

8.  Ishii, K., Nagaoka, A., Kishida, K., Okazaki, H., Yagishita, S., Ucar, H., Saito, N. & Kasai, H. (2018). Volume dynamics of dendritic spines in the neocortex of wild type and Fmr1 KO mice in vivo. eNeuro 5, e0282-18.2018:1-13.   

We measured the fluctuations of spines in vivo adult neocortex, where big spines fluctuated more, and the fluctuations were exacerbated in an ASD model (FMRP-KO). Interestingly, small spines show disproportionately little fluctuations, which resulted in suppressed spine turn-overs in the adult neocortex.

9.  Okazaki,H., Hayashi-Takagi, A., Nagaoka, A., Negishi, M., Ucar, H., Yagishita, S., Ishii, K., Toyoizumi, T., Fox, K., & Kasai, H. (2018) Calcineurin knockout mice show a selective loss of small spines, Neurosci Lett 671:99-102. 

Despite the fact that  spine shrinkage was suppressed in CNBKO mice, the spine sizes were not severely affected. In fact, they were only slightly enlarged, and comprised of less small spines, supporting the impairment of working memory in the mice. The phenomena also exemplified the importance of spine fluctuations in size distributions.

10. Noguchi, J., Hayama, T., Watanabe, S., Ucar, H., Yagishita, S., Takahashi, N. & Kasai, H. (2016) State-dependent diffusion of actin-depolymerizing factor/cofilin underlies the enlargement and shrinkage of dendritic spines. Scientific Reports 6: 32897.   

Spine enlargement occurs selective to stimulated spines where phosphorylated cofilin accumulates such as in the stress fiber. In contrast, spine shrinkage spreads to the neighboring spines by diffusion of dephosphorylated cofilin which severs actin fibers.

11. Nagaoka, A., Takehara, H., Hayashi-Takagi, A., Shirai, F., Ishii, K., Noguchi, J., Ichiki, K. & Kasai, H. (2016) Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo.  Scientific Reports 6: 26651.  

Spine turnovers are accelerated in ASD models. We examined whether they were caused by activity-dependent plasticity, and found that they not blocked by local superfusion of APV, TTX and VDCC inhibitors in neocortex in vivo. The exacerbated fluctuations cause the larger turnovers and smaller spines in ASD.

12. Hayashi-Takagi, A., Yagishita, S., Nakamura, M. Shirai, F., Wu, Y., Loshbaugh, A.L., Kuhlman, B., Hahn, K.M. and Kasai, H. (2015). Labelling and optical erasure of synaptic memory traces in the motor cortex. Nature 525: 333-338.　

We constructed the synaptic optoprobe (AS-probes) that  labelled the enlarged spines by learning, and erased them by blue laser irradiation. We found that the motor memory was eliminated after removal of enlarged spines by blue laser irradiation of AS-probes. We found a small fraction of neurons and spines are involved in a specific memory.       F1000 Recommendations

13. Yagishita, S., Hayashi-Takagi, A., Ellis-Davies, G.C.R., Urakubo, H., Ishii, S., and Kasai, H. (2014).A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science 345:1616-1620.

Dopamine D1 receptors detected a temporal contingency between pre-post spikes  and a transient increase in dopamine concentrations, and induced spine enlargement in the striatum, consistent with the reward timing in the classical conditioning. AC1 plays the central role in the timing detection.        F1000 Recommendations

14. Hayama, T., Noguchi, J., Watanabe, S., Ellis-Davies, G.C.R., Hayashi, A., Takahashi, N., Matsuzaki, M. & Kasai, H. (2013). GABA promotes the competitive selection of dendritic spines by controlling local Ca2+ signaling.  Nature Neurosci. 16:1409-1416. 

Shrinkage of dendritic spines was induced by STDP stimulation only when GABAA receptors are stimulated to suppress the global increases in Ca2+. Such shrinkage could even lead to elimination, which spread to neighboring spines up to 20 um. Thus, we found spine shrinkage is non-Hebbian plasticity, and effectively eliminate unused synapses.      F1000 Recommendations

15. Noguchi, J., Nagaoka, A., Watanabe, S., Ellis-Davies, G.C.R., Kitamura, K., Kano, M., Matsuzaki, M. & Kasai H. (2011). In vivo two-photon uncaging of glutamate revealing the structure-function relationships o f dendritic spines in the neocortex of adult mice. J.Physiol. 589,2320-2329. 

We established in vivo two-photon uncaging of glutamate, and revealed the tight structure-function relationship of dendritic spine in vivo neocortex. 

16. Kasai, H., Fukuda, M, Watanabe, S., Hayashi-Takagi, A. & Noguchi, J. Structural dynamics of dendritic spines in memory and cognition. Trends Neurosci. 33, 121-129. 

A seminal review for dendritic spine.  (cited 663)

17. Yasumatsu N, Matsuzaki M, Miyazaki T, Noguchi J, Kasai, H (2008). Principles of long-term dynamics of dendritic spines. J. Neurosci. 28, 13592-13608. PubMed　

The discovery of the spontaneous fluctuations of spine that govern the spine size distributions.  Daily dynamics of spine volume are correlated with spine volume distributions using Langevin equations.

18. Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies GCR, Kasai, H (2008).The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines.  Neuron 57, 719-729. 

Spine motility is based on three pools of actin fibers, dynamic, stable and enlargement pools with distinct turnover rates (40s and 15min). Stable pool normally localized at the base of the spine head, while the enlargement pool spreads and causes spine enlargement. Note：Actin fibers in motile spines          F1000 Recommendations

19. Tanaka, J., Horiike, Y., Matsuzaki, M., Miyazaki, T., Ellis-Davies, GCR & Kasai, H. (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683-1687.

Spine enlargement involved the protein-synthesis dependent component when it was induced by spike timing protocol, which induced spike in the postsynaptic neurons. BDNF signaling is necessary for the protein synthetic processes.

20. Noguchi,J., Matsuzaki,M., Ellis-Davies, G.C.R. & Kasai, H. (2005).Spine-neck geometry determines NMDA receptor-dependent Ca2+ signaling in dendrites.  Neuron 46, 609-622. 

Spine neck is the major controller of the Ca signal in the spine head for NMDA receptor functions, and amplify Ca increases in small spines.          F1000 Recommendations

21. Matsuzaki, M., Honkura, N., Ellis-Davies,G.C.R., & Kasai,H. (2004).Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761-766. 

Discovery of spine enlargement as the basis for long-term potentiation (LTP).     F1000 Recommendations

22. Matsuzaki,M., G.C.R. Ellis-Davies, Nemoto,T., Miyashita,Y., Iino,M. & Kasai,H. (2001).Dendritic spine geometry is critical for AMPA receptors expression in hippocampal CA1 pyramidal neurons. Nature Neurosci. 4, 1086-1092. 

Development of two-photon glutamate uncaging method to study single dendritic spines.

23. Maeda, H., Ellis-Davies, G.C.R., Ito, K., Miyashita, Y. & Kasai, H. (1999). Supralinear Ca2+ signaling by cooperative and mobile Ca2+ buffering in Purkinje neurons. Neuron 24, 989-1002. 

Features and roles of high-affinity Ca buffers in the cerebellar Purkinje cells.

24.  Mori, A., Takahashi, T., Miyashita, Y. & Kasai, H. (1994).  Two distinct glutamatergic synaptic inputs to the striatal medium spiny neurones of neonatal rat and paired-pulse depression. J. Physiol. 476,217-228. 

The discovery of glutamatergic interneurons in the striatum. The neurons turned out to be the cholinergic interneurons, Higley et al. (2011) PLoS 6:e19155

25. Toyama, K., Komatsu, Y., Kasai, H., Fujii, K. & Umetani, K. (1985). Responsiveness of Clare-Bishop neurons to visual cues associated with motion of a visual stimulus in the three-dimensional space.  Vision Res. 25, 407-414. 

The roots of all my studies:  Unit recording of the MT (Clare-Bishop) area in anesthetized cat. 

Presynaptic dynamics

1. Takahashi, N.,Sawada w,  Noguchi, J., Watanabe, S., Ucar, H., Hayashi-Takagi, A., Yagishita, S., Ohno, M., Tokumaru, H. & Kasai, H. (2015).Two-photon fluorescence lifetime imaging of primed SNARE complexes in presynaptic terminals and β cells. Nature Communcations 6, 8531. 

Direct demonstration of SNARE assembly using intermolecular FRET by two-photon fluorescence lifetime imaging (FLIM).  SNARE assembly before stimulation was found only in presynaptic terminals but not in  β cells.  Note: New imaging method for exocytosis, using both N-terminal and C-terminal intermolecular FRET probes for SNAREs.

2. Kasai, H., Takahashi, N. & Tokumaru, H. (2012). Distinct initial SNARE configurations underlying the diversity of exocytosis.  Physiol. Rev. 92,1915-1964. 

In this review, we present many lines of evidence indicating the importance of stimulus induced assembly of SNAREs, with the notable exception of the presynaptic terminal where exocytosis occurs in a fraction of one mili-second.

3. Takahashi, N., Hatakeyama, H., Okado, H., Noguchi, J. Ohno, M. & Kasai, H. (2010).SNARE conformational changes that prepare vesicles for exocytosis. Cell Metabolism 12:19-29.  

News: Solimena, M. & Speier, S. (2010) Shedding light on a complex matter. Cell Metabolism12:5-6. 

SNARE assembly was induced after stimulation in insulin secreting β cells in the inslet of Langerhans.           F1000 Recommendations

4. Kishimoto, T., Kimura, R., Liu.T.-T., Nemoto, T., Takahashi, N. & Kasai, H.(2006).Vacuolar sequential excocytosis of large dense-core vesicles in adrenal medulla. EMBO J. 25, 673-682. PubMed

Discovery of compound exocytosis in adreanl chromafin cells where granular contents swoll after exocytosis and facilitated the compound exocytosis. The phemenon is named "vacuolar sequential exocytosis" and the first demonstration of mechanical effects on exocytosis.

5. Takahashi,N., Kishimoto,T., Nemoto,T., Kadowaki,T. & Kasai,H. (2002).Fusion pore dynamics and insulin granule exocytosis in the pancreatic islet. Science 297, 1349-52. 

First visualization of insulin exocytosis in the islet of Langerhans. Exocytosis occurred mostly toward intercellular space not facing vessels, as a full-fusion event, and the initial fusion pore (1.4 nm) appears to be lipidic.

6. Nemoto, T., Kimura, R., Ito, K., Tachikawa, A., Miyashita, Y., Iino, M. & Kasai, H. (2001). Sequential replenishment mechanism of exocytosis in pancreatic acini.  Nature Cell Biology 3, 253-258. 

Discovery of sequential exocytosis, and its live two-photon imaging in exocrine pancreas.

7. Kasai, H. (1999). Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function. Trends in Neurosciences 22, 88-93. 

A review on the diversity of exocytosis in various secretory cells.

8. Takahashi,N., Kadowaki, T., Yazaki,Y., Ellis-Davies, G.C.R., Miyashita, Y. & Kasai, H. (1999). Post-priming actions of ATP on Ca2+-dependent exocytosis in pancreatic beta cells. Proc. Natl. Acad. Sci. U.S.A. 96, 760-765. 

The ATP and cAMP regulation of exocytosis in insulin secreting beta cells.  ATP-γS was similarly effective as ATP, suggesting insulin exocytosis senses glucose and cytosolic ATP via cAMP dependent control of insulin exocytosis.

9. Kasai, H., Li, Y. & Miyashita, Y. (1993).  Subcellular distribution of Ca2+ release channels underlying Ca2+ waves and oscillations in exocrine pancreas. Cell 74, 669-677. 

Effective cytosolic diffusion and heterogenous IP3 receptor distribution as major reasons for the Ca waves in exocrine cells (Confocal microscope).

10. Kasai, H. & Augustine, G. J. (1990). Cytosolic Ca2+ gradients triggering unidirectional fluid secretion from exocrine pancreas. Nature 348, 735-738. DOI:10.1038/348735a0 

Discovery of global Ca2+ waves in exocrine pancreas by Ca2+ imaging (SIT camera). My work in Germany.

11. Kasai, H. & Neher, E. (1992).  Dihydropyridine-sensitive and ω-conotoxin-sensitive calcium channels in a mammalian neuroblastoma-glioma cell line.  J. Physiol. 448, 161-188.

12. Aosaki, T. & Kasai, H.  (1989).  Characterization of two kinds of high-voltage-activated Ca-channel currents in chick sensory neurons. Pflügers Archiv 414, 150-156.  

13.  Kasai, H., Aosaki, T. & Fukuda, J. (1987).  Presynaptic Ca-antagonist ω-conotoxin irreversibly blocks N-type Ca-channels in chick sensory neurons.  Neurosci. Res. 4, 228-235.

The first report of the selective blockade of N-type voltage gated Ca2+ channels (Cav2.2.) but not L-type channels (Cav1.3) with ω-conotoxin VIA.  Richard Tsien originally proposed the toxin blocked both channels (Fox et al. 1987, JP) , but my conclusion is now universally accepted.

14.  Kasai, H., Kameyama, M., Yamaguchi, K. & Fukuda, J. (1986).  Single transient K channels in mammalian sensory neurons. Biophys. J. 49, 1243-1247. 

The first report of single-channel recording of A type K channels (Kv1.4), my PhD thesis.