Graduate School of Medicine / School of Medicine, Faculty of Medicine

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Medical Neuroscience

Neurophysiology and Neural Repair

The cerebellum plays an important role in coordinated movement, motor learning and vestibular function. Cerebellar damage results in impaired body balance and disturbance in gait and posture. Our aim is to elucidate pathophysiology of the cerebellum. One major disease target is “spinocerebellar ataxia (SCA)”, which is currently an incurable disease. Approximately one third of the SCA in patients is hereditary. So far, at least 29 types of SCA result from chromosomal loci of the causal genes (Carlson et al., 2009), in which the major lesion of SCA type 1 (SCA1), SCA2, SCA6, SCA14, SCA17 and SCA31 affects Purkinje cells. Using viral vectors, we have developed methods that allow for Purkinje cell-specific gene expression in mice. Using the newly developed gene transfer method for the cerebellum, we have succeeded to alleviate severe ataxia of SCA type 3 model mice by introducing a therapeutic gene. We are further working on this subject, including translation of the therapy into clinic. Research techniques in our laboratory include patch clamp recording, molecular biology, development of lentiviral/AAV vectors, protein chemistry, immunohistochemistry and behavioral experiments.

  • Staff
  • Research & education
  • Clinical Activities
  • Citizen Activities
  • Achievement
  • History

Staffs

Professor Hirokazu Hirai, M.D.,Ph.D.  
Associate Professor Kazuhiro Nakamura, M.D.,Ph.D.  
Assistant Professor Nobutake Hosoi, Ph.D.  
  Akira Iizuka, Ph.D.  
  Ayumu Konno,Ph.D.  

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Research & Education

Research content

• Development of viral vector-based efficient and cell-type specific gene transfer/expression system
AAV and lentiviral vectors
• Development of novel therapies against SCAs
Gene therapy and stem cell therapy
• Elucidation of molecular mechanisms regulating the cerebellar development
Dendritogenesis and synaptogenesis of Purkinje cells
Generation and analysis of gene-modified animals

Business education

Undergraduate students:
1. General physiology
(For the 2nd grade students of School of Medicine)
Lectures of biophysics and membrane physiology.
2. Neurophysiology
(For the 3rd grade students)
Lectures and laboratory courses of neurophysiology (functions of the central and peripheral nervous systems and skeletal muscles)
3. Pathophysiology
(For the 3rd grade students)
Lectures of pain, disturbance of sensation, headache, ataxia, and
vertigo & dizziness.

Postgraduate students:
1. Electrophysiological training
Whole-cell patch-clamp recordings in acute brain slices.
Single-channel recordings and whole-cell patch-clamp recordings in cultured hippocampal and cerebellar neurons, and glial cells.
2. Molecular biological training
PCR amplification of cDNAs obtained from single cells, handling of viral vectors
3. Training for animal experiments

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Clinical Activities

We cooperate the work of department of clinical genetics in Gunma University Hospital.

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Citizenship Activities

Prof. Hirai is a medical adviser of the Japanese association for SCA & MSA patients.

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Achievements

Oue M, Handa H, Matsuzaki Y, Suzue K, Murakami H, Hirai H.
The Murine Stem Cell Virus Promoter Drives Correlated Transgene Expression in the Leukocytes and Cerebellar Purkinje Cells of Transgenic Mice.
PLoS ONE 7(11): e51015. doi:10.1371/journal.pone.0051015

Goenawan H, Hirai H.
Modulation of lentiviral vector tropism in cerebellar Purkinje cells in vivo by a lysosomal cysteine protease cathepsin K.
Journal of NeuroVirology 18(6):521-31, 2012

Hirai H.
Basic research on cerebellar gene therapy using lentiviral vectors.
Cerebellum 11(2):443-5, 2012

Mitsumura K, Hosoi N, Furuya N, Hirai H.
Disruption of metabotropic glutamate receptor signalling is a major defect at cerebellar parallel fibre-Purkinje cell synapses in staggerer mutant mice.
The Journal of Physiology 589:3191-3209, 2011

Shuvaev AN, Horiuchi H, Seki T, Goenawan H, Irie T, Iizuka A, Sakai N, Hirai H.
Mutant PKC{gamma} in spinocerebellar ataxia type 14 disrupts synapse elimination and long-term depression in Purkinje cells in vivo.
The Journal of Neuroscience 31(40):14324-34, 2011

Sasaki J et al.
The PtdIns(3,4)P(2) phosphatase INPP4A is a suppressor of excitotoxic neuronal death.
Nature 465(7297):497-501, 2010
Sawada Y, Kajiwara G, Iizuka A, Takayama K, Shuvaev AN, Koyama C, Hirai H.
High Transgene Expression by Lentiviral Vectors Causes Maldevelopment of Purkinje Cells in Vivo.
Cerebellum 9(3):291-302, 2010

Iizuka A, Takayama K, Torashima T, Yamasaki M, Koyama C, Mitsumura K, Watanabe M, Hirai H.
Lentiviral vector-mediated rescue of motor behavior in spontaneously occurring hereditary ataxic mice.
Neurobiology of Disease 35(3):457-65, 2009

Hirai H.
Progress in transduction of cerebellar Purkinje cells in vivo using viral vectors.
The Cerebellum 7(3):273-8, 2008

Torashima T, Koyama C, Iizuka A, Mitsumura K, Takayama K, Yanagi S, Oue M, Yamaguchi H, Hirai H.
Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia.
EMBO Reports 9(4):393-9, 2008

Jin D*, Liu HX*, Hirai H* et al.(*equally contributed)
CD38 is critical for social behaviour by regulating oxytocin secretion.
Nature 446(7131):41-5, 2007

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History

1) In 1954, the 2nd department of physiology was founded in Gunma University School of Medicine, and Dr. Sadayuki Takagi was appointed to the first professor. The specialty of Prof. Takagi was the sensory neurophysiology, and he and staffs of the department have made a great contribution to the progress in olfactory physiology.
2) In 1984, after the retirement of Prof. Takagi, Dr. Seiji Ozawa took over the duties. Dr. Ozawa’s specialties were neurophysiology and cellular physiology, and the research of the department has been focused on the function and molecular structures of glutamate receptors in the CNS. Using electrophysiological and molecular biological methods, he and his group have established that AMPA-type glutamate receptors are divided into two groups with different Ca2+ permeability.
3) In 2003, Gunma University Graduate School of Medicine was established by the restructuring of Gunma University School of Medicine, and accordingly the name of the department was changed to Department of Neurophysiology.
4) In 2006, Dr. Hirai was appointed to the third professor, and took over the duties from Prof. Ozawa. He decided the targets of research to be the elucidation of pathophysiology of cerebellar disorders.