| 翻訳と辞書 |
| Glutamate hypothesis of schizophrenia ： ウィキペディア英語版 |
Glutamate hypothesis of schizophrenia
The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.
Like the dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, NMDA antagonists mimic some positive and negative symptoms with less brain harm. Likely, both dopaminergic and glutaminergic abnormalities are implicated in schizophrenia, from a profound alteration in the function of the chemical synapses, as well as electrical synaptic irregularities. These form a portion of the complex constellation of factors, neurochemically, psychologically, psychosocially, and structurally, which result in schizophrenia.
==GPCRs and Schizophrenia==
We know that hypofunctioning glutamate receptors are a contributing factor in developing schizophrenia (Mechri, A 2001). Alterations in the expression, distribution, autoregulation,(Catapano, L Manji, H, 2006) prevalence of specific heterodimers,(Gonzales, 2012) and relative levels of G proteins, specifically lowered levels of the i isomorph,(F Odaka, T.J Crow, G.W Roberts) all can result in an altered NMDA function. The primary contributor to schizophrenia is a relative deficit of presynaptic glutamate receptors to the postsynaptic receptors. Specifically, group II is indicated in this disorder, given that mGlu2/3 agonists have been found useful in the treatment of both positive and negative symptoms. However, all regulatory neurotransmitters are involved, as every metabotropic receptor has potential to alter glutaminergic function.(Sugai, 2006) Specifically, 5-HT has an extraordinarily wide role in modulatory processes of the brain, as such, it is highly implicated in all CNS function. In addition, CB1 plays a global inhibitory role, serving to inhibit the release of all neurotransmitters. In addition, CB1 is one of the most widely distributed receptors in the brain, thus, downregulation of this receptor will increase global chemical synaptic activity. No difference in expression or distribution is observed, but when the CB1 receptor develops a tolerance, 2-AG(full) cannot exert its full inhibitory effects on GABA and glutamate release. A deficit in endocannobinoid metabolism, or excess catabolism, as well as heavy cannabis use, will deregulate global chemical transmission.
This is the key in schizophrenia: the fact that this deregulates glutamate carboxylase expression, which acts to downregulate reelin production, the crucial mediator of neurogenesis. Specifically, the reelin expressing Cajal-Retzius cells are of interest. These cells are a crucial component of (corticocortical ) transmission, due to their long, nearly horizontal axons, multiple synapses, and consistent termination on spiny pyramidal neurons. These allow for interlayer communication over a wider area than those without, e.g. chimpanzees. This is the part of the neurological system which is most different, and the part of the genome which is most "accelerated" vs chimpanzees. This would indicate that this is a necessary factor for the development of the so-called speech centers of the brain, Wernickie's and Broca's areas. Also, a deficit in reelin activity is associated with cortical developmental retardation. These neurons also express 5-HT3 significantly, which is the only serotonergic ligand gated ion channel. Presynaptically, they act to regulate neurotransmitter release, mediating the frequency and strength of tonic firing in connected neurons. This is likely the mechanism through which they mediate long term potentiation. A deficit in this activity would alter plasticity significantly, contributing to the illnesses of bipolar disorder and schizophrenia.
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
■ウィキペディアで「Glutamate hypothesis of schizophrenia」の詳細全文を読む
スポンサード リンク
| 翻訳と辞書 : 翻訳のためのインターネットリソース |
Copyright(C) kotoba.ne.jp 1997-2016. All Rights Reserved.
|
|