第50回名古屋神経病理アカデミー 2013年7月13日


テーマ「精神疾患と神経疾患の再癒合」進行:入谷 修司(名古屋大学)

「統合失調症死後脳研究の時代―From the graveyard to the fertile ground―」

名古屋大学精神医学 尾崎紀夫先生


昭和大学神経内科 河村 満先生





症例2.Frontotemporal dementia(FTD)


VELAKOULIS, D., et al. Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: clinicopathological series and review of cases. The British Journal of Psychiatry, 2009, 194.4: 298-305.


症例3 抗NMDA受容体脳炎 16歳女性




IRITANI, Shuji, et al. Immunohistochemical study of vesicle monoamine transporter 2 in the hippocampal formation of PCP-treated mice. Neuroscience research, 2010, 68.2: 125-130.

Neurodevelopment modelについて



Excitatory – (?)の増加

INSEL, Thomas R. Rethinking schizophrenia. Nature, 2010, 468.7321: 187-193.


RAPOPORT, J. L.; GIEDD, J. N.; GOGTAY, N. Neurodevelopmental model of schizophrenia: update 2012. Molecular psychiatry, 2012, 17.12: 1228-1238.





FLYNN, S. W., et al. Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Molecular psychiatry, 2003, 8.9: 811-820.


TKACHEV, Dmitri, et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. The Lancet, 2003, 362.9386: 798-805.


HÖISTAD, Malin, et al. Linking white and grey matter in schizophrenia: oligodendrocyte and neuron pathology in the prefrontal cortex. Frontiers in neuroanatomy, 2009, 3.


receptor protein tyrosine phosphatase α(RPTPα)と統合失調症尾崎先生の教室の仕事。

Ptpra⁻/⁻ miceは統合失調症症状を示し、myelination関連遺伝子を減少させた。RPTPA遺伝子部位の多型が統合失調症と関連していた。患者死後脳でのRPTPαのmRNAがdorsolateral prefrontal cortexで低下していた。

Takahashi N, et al. Loss of function studies in mice and genetic association link receptor protein tyrosine phosphatase α to schizophrenia. Biol Psychiatry. 2011;70(7):626-35.



Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness.


We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases).


We found that Ptpra⁻/⁻ mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ.


The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.


TAKAHASHI, Nagahide, et al. Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia. Progress in neurobiology, 2011, 93.1: 13-24.

In conclusion, imaging, anatomical, molecular, and genetic evidence indicate that there is an abnormality in oligodendrocyte/myelin in schizophrenia, and it is becoming clear that oligodendrocyte loss/dysmyelination is a primary deficit in the disorder and can lead to the several neuronal deficits observed in schizophrenia, such as altered synaptic function and altered circuitry. A further understanding of the role of oligodendrocyte/myelin in schizophrenia would provide new insights into the treatment of this disease.


田中謙二,池中一裕: 白質の可塑性と疾患の関わり 実験医学 VoL28 No.5(増刊)830, 2010

一時oligodendrocyte maniaになっていた自分が統合失調症の分野でこのような進展があったことを知り、衝撃的な知的興奮を感じた。





WHITFORD, Thomas J., et al. Schizophrenia, myelination, and delayed corollary discharges: a hypothesis. Schizophrenia bulletin, 2012, 38.3: 486-494.


Any etiological theory of schizophrenia must account for at least 3 distinctive features of the disorder, namely its excessive dopamine neurotransmission, its frequent periadolescent onset, and its bizarre, pathognomonic symptoms. In this article, we theorize that each of these features could arise from a single underlying cause—namely abnormal myelination of late-developing frontal white matter fasciculi. Specifically, we suggest that abnormalities in frontal myelination result in conduction delays in the efference copies initiated by willed actions. These conduction delays cause the resulting corollary discharges to be generated too late to suppress the sensory consequences of the willed actions. The resulting ambiguity as to the origins of these actions represents a phenomenologically and neurophysiologically significant prediction error. On a phenomenological level, the perception of salience in a self-generated action leads to confusion as to its origins and, consequently, passivity experiences and auditory hallucinations. On a neurophysiological level, this prediction error leads to the increased activity of dopaminergic neurons in the midbrain. This dopaminergic activity causes previously insignificant events to be perceived as salient, which exacerbates the budding hallucinations and passivity experiences and triggers additional first-rank symptoms such as delusions of reference. The article concludes with a discussion of the implications of the theory and some testable predictions which may form a worthwhile basis for future research.




先日、順天堂大学神経内科の服部教授の講演を聞く機会があった。パーキンソン病の発症機序について、まだ論文になっていない内容や、投稿中の研究成果を披露してくださり、ひさしぶりに知的な興奮を覚えた。内容についてはここには書けないが、ぼくは5つの質問を投げかけた。最先端の研究をやっていて、世界の他の研究者との競争が激しくて、最初にめざしていたジャーナルでは論文が採用されなかったとか、chief editorとの意見の違いなどを話された。




http://blog.with2.net/link.php/36571 (ブログランキングに登録していますのでよろしく)


marugametorao について

神経内科専門医 neurologist
カテゴリー: 神経内科医, 神経学, 健康, 医学 パーマリンク



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