1: Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia

Cell Rep Med.

2023 Oct 17;4(10):101208. doi: 10.1016

Yoshifumi Abe, Sho Yagishita, Hiromi Sano, Yuki Sugiura, Masanori Dantsuji, Toru Suzuki, Ayako Mochizuki, Daisuke Yoshimaru, Junichi Hata, Mami Matsumoto, Shu Taira, Hiroyoshi Takeuchi, Hideyuki Okano, Nobuhiko Ohno, Makoto Suematsu, Tomio Inoue, Atsushi Nambu, Masahiko Watanabe, Kenji F Tanaka

Involuntary writhing movements of the body and mumbling of the mouth are called dyskinesia. Dyskinesia can occur both when dopamine antagonists are administered for diseases that may involve increased dopamine (schizophrenia), resulting in tardive dyskinesia, and when dopamine agonists are administered for diseases with decreased dopamine (Parkinson's disease), resulting in L-DOPA-induced dyskinesia. What is the common pathology underlying these conditions that arise under completely different circumstances? Based on the idea that there must be an abnormal brain structure linked to these abnormal movements, we anatomically examined the brains of mouse models for each condition and found that hypertrophy of striatal projection neuron terminals was a common pathology. We found that this terminal hypertrophy can be explained by an increase in a molecule called vesicular GABA transporter (VGAT), and that this increase leads to enhanced GABA release from striatal neurons, causing dyskinesia. We also found that striatal VGAT expression increases when inhibition of D2 receptor signaling in striatal neurons is combined with repeated fluctuations in extracellular dopamine levels. Furthermore, we revealed that valbenazine, a treatment for tardive dyskinesia, exerts its therapeutic effect by suppressing the increase in extracellular dopamine levels. This is an example of reaching the truth by deeply investigating morphological abnormalities.

(Kenji F. Tanaka, Professor, Division of Brain Science, Institute for Advanced Medical Research (Class of '76); Yoshifumi Abe, Lecturer; Hiroyoshi Takeuchi, Associate Professor, Department of Neuropsychiatry)

Nat Cell Biol.

2023 Oct;25(10):1415-1425. doi: 10.1038

Takahito Iga, Hiroshi Kobayashi, Dai Kusumoto, Tsukasa Sanosaka, Nobuyuki Fujita, Ikue Tai-Nagara, Tomofumi Ando, Tomoko Takahashi, Koichi Matsuo, Katsuto Hozumi, Kosei Ito, Masatsugu Ema, Takeshi Miyamoto, Morio Matsumoto, Masaya Nakamura, Hideyuki Okano, Shinsuke Shibata, Jun Kohyama, Kevin K. Kim, Keiyo Takubo & Yoshiaki Kubota

Bones not only support the body and protect internal organs like the brain, but their interior (bone marrow) also contains hematopoietic stem cells that produce blood cells such as red and white blood cells daily and deliver them throughout the body. The blood vessels in the bone marrow are crucial for both this skeletal role and the role of blood production. However, unlike soft tissues, the task of "slicing sections" of bone for detailed observation is difficult due to its hardness. Consequently, our understanding of bone marrow blood vessels has lagged behind that of vessels in other organs. Through improvements in conventional tissue sectioning methods, single-cell analysis, and the creation of new genetically modified mice, this study discovered a previously unknown subtype of bone marrow blood vessels in the end of the bone (the epiphysis) that is important for bone development and blood production. Although the epiphysis is a critical site in human diseases such as femoral neck fractures and avascular necrosis of the femoral head, it has traditionally been cut off with scissors and discarded for convenience when analyzing mouse bones and bone marrow, and thus has been largely unstudied. In the future, the discovery of this unique vascular subtype is expected to advance our understanding of these diseases.

(Yoshiaki Kubota, Department of Anatomy (Class of '79); Takahito Iga, Department of Orthopaedic surgery (Class of '91))