http://molecular-ethology.biochem.s.u-tokyo.ac.jp/neuro-seminar/ftp-box/coagonist.pdf

Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists

Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.

/pdf/molecular-mechanisms-of-schizophrenia-519uzgf6dp.pdf

Molecular mechanisms of schizophrenia.

We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.

https://www.pnas.org/content/pnas/107/16/7556.full.pdf

Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase

D-amino acids in the central nervous system in health and disease.

http://neurobehaviour.lunenfeld.ca/files/file/Duffy%20et%20al%202008%20Neuropsychopharmacology.pdf

D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning.

Exaggerated responses to chronic nociceptive stimuli and enhancement of N-methyl-D-aspartate receptor-mediated synaptic transmission in mutant mice lacking D-amino-acid oxidase.

巨大卵巣嚢腫のため,仰臥位での睡眠が困難な症例の周術期管理を経験した.術前にあらかじめ約35lの嚢腫内容液を排除したところ,仰臥位での睡眠が可能となった.手術を全身麻酔下に開始したが,嚢腫内容液の吸引により血圧は低下し,昇圧薬と急速輸液で対処した.同時に低酸素血症を呈したため,一時的に高濃度酸素吸入を行なった.術前排液量を含めた摘出臓器重量は53kgであった.術後は集中治療部にて管理したが,入室8時間後に血圧低下をきたした以外,呼吸・循環系は安定しており,術後2日目に集中治療部を退室し,後日軽快退院した.

https://www.jstage.jst.go.jp/article/jjsca1981/17/2/17_2_116/_pdf

Shinji Hanzawa

Papers

Exaggerated responses to chronic nociceptive stimuli and enhancement of N-methyl-D-aspartate receptor-mediated synaptic transmission in mutant mice lacking D-amino-acid oxidase.

Perioperative Management in a Patient with Giant Ovarian Cyst