Cholinesterases are fundamental players in the peripheral and central nervous systems [...].
- MeSH
- Acetylcholinesterase genetics metabolism MeSH
- Butyrylcholinesterase genetics metabolism MeSH
- Central Nervous System cytology drug effects enzymology MeSH
- Cholinesterase Inhibitors therapeutic use MeSH
- Gene Expression MeSH
- GPI-Linked Proteins genetics metabolism MeSH
- Humans MeSH
- Synaptic Transmission MeSH
- Neurodegenerative Diseases drug therapy enzymology genetics pathology MeSH
- Neurons cytology drug effects enzymology MeSH
- Neuroprotective Agents therapeutic use MeSH
- Peripheral Nervous System cytology drug effects enzymology MeSH
- Synapses drug effects enzymology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Editorial MeSH
Cholesterol is a structural component of cellular membranes particularly enriched in synapses but its role in synaptic transmission remains poorly understood. We used rat hippocampal cultures and their acute cholesterol depletion by methyl-β-cyclodextrin as a tool to describe the physiological role of cholesterol in glutamatergic synaptic transmission. Cholesterol proved to be a key molecule for the function of synapses as its depletion resulted in a significant reduction of both NMDA receptor (NMDAR) and AMPA/kainate receptor-mediated evoked excitatory postsynaptic currents (eEPSCs), by 94% and 72%, respectively. We identified two presynaptic and two postsynaptic steps of synaptic transmission which are modulated by cholesterol and explain together the above-mentioned reduction of eEPSCs. In the postsynapse, we show that physiological levels of cholesterol are important for maintaining the normal probability of opening of NMDARs and for keeping NMDARs localized in synapses. In the presynapse, our results favour the hypothesis of a role of cholesterol in the propagation of axonal action potentials. Finally, cholesterol is a negative modulator of spontaneous presynaptic glutamate release. Our study identifies cholesterol as an important endogenous regulator of synaptic transmission and provides insight into molecular mechanisms underlying the neurological manifestation of diseases associated with impaired cholesterol synthesis or decomposition.
- MeSH
- Receptors, AMPA metabolism MeSH
- Cholesterol pharmacology MeSH
- Excitatory Postsynaptic Potentials drug effects MeSH
- Hippocampus drug effects metabolism MeSH
- Rats MeSH
- Glutamic Acid metabolism MeSH
- Cerebral Cortex drug effects metabolism MeSH
- Synaptic Transmission * MeSH
- Neurons drug effects metabolism MeSH
- Rats, Wistar MeSH
- Presynaptic Terminals drug effects metabolism MeSH
- Receptors, N-Methyl-D-Aspartate metabolism MeSH
- Synapses drug effects metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Keywords
- synaptogeneze,
- MeSH
- Anesthetics, Dissociative pharmacology adverse effects therapeutic use MeSH
- Excitatory Amino Acid Antagonists pharmacology adverse effects therapeutic use MeSH
- Antidepressive Agents pharmacology adverse effects therapeutic use MeSH
- Bipolar Disorder drug therapy MeSH
- Anesthesia, General MeSH
- Depressive Disorder, Treatment-Resistant drug therapy MeSH
- Depressive Disorder, Major drug therapy MeSH
- Depressive Disorder * drug therapy MeSH
- Ketamine * pharmacology adverse effects therapeutic use MeSH
- Humans MeSH
- Brain-Derived Neurotrophic Factor drug effects MeSH
- Neuronal Plasticity * drug effects MeSH
- Receptors, N-Methyl-D-Aspartate drug effects MeSH
- Suicidal Ideation MeSH
- Synapses drug effects MeSH
- TOR Serine-Threonine Kinases MeSH
- Drug Administration Routes MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Epigenetika se zabývá tím, jak zevní i vnitřní faktory ovlivňují funkci DNA daného organizmu, aniž by se přitom měnila její sekvence. Epigenetické vlivy jsou významné jak v buňkách stávajících, tak dceřiných, a to v rámci jedince i mezigeneračního přenosu získaných znaků. Za nejvýznamnější epigenetické mechanizmy bývají považovány acetylace histonů a metylace DNA, k nim však přistupuje řada dalších molekulárních procesů. Vedle epigenetiky je dalším odvětvím molekulární biologie výzkum nekódující RNA, který se začíná uplatňovat také ve studiu psychických poruch. Nekódující RNA, vznikající především z tzv. nesmyslné DNA, ovlivňuje genovou expresi. I Epigenetické výzkumy doposud byly prováděny jen na tkáních in vitro, pokusných zvířatech a zemřelých nemocných. Chybí epigenetické klinické studie. Do budoucna se jako nadějná jeví epigenetická terapie kognitivních poruch, schizofrenie a poruch nálady. Přitom je možno využívat jak léků stávajících (např. valproát, klozapin, sulpirid, escitalopram, lithium), tak látek nově syntetizovaných. Problémem je, že epigenetické účinky uvedených látek nejsou topicky, tkáňově, enzymaticky či genově specifické. To může vést k závažným nežádoucím účinkům. V budoucnu je zapotřebí vyrábět substrátově specifická farmaka s epigenetickými účinky a začít jejich testování na lidech. Epigenetika nám může napomoci při překonávání farmakorezistence duševních poruch, případně v jejich časné detekci a prevenci.
Epigenetics deals with the influence of external as well as intrinsic factors on the DNA function in a given organism without t he chan- ge of DNA sequence. Epigenetic effects are significant in both currently existing cells and their daughter cells. This holds tr ue for an individual organism as well as intergenerational transmission of acquired signs. Histone acetylation and DNA methylat ion are considered as the most important epigenetic mechanisms. In addition to this, other molecular procedures have already been recognized, including non-coding RNA molecules which influence gene expression. Non-coding RNA is mostly synthesized based on so called nonsense DNA. Epigenetic research has only been performed on in vitro tissues, experimental animals and brain tissue of decea- sed psychiatric patients so far. Clinical epigenetic studies in the treatment of mental disorders are lacking. Epigenetic thera py of cognitive disorders, schizophrenia, and mood disorders seems to be promising for the future. In this effort, both existing medi caments (valproate, clozapine, sulpiride, escitalopram, lithium) and newly synthesized chemical substances can be utilized. The problem is that epigenetic effects of currently known substances are not specific for individual parts of the brain, brain cells, enzymes or ge nes. This may induce serious adverse effects. In the future, it is necessary to produce substrate-specific epigenetic medicaments, and start epigenetic cli- nical studies. Epigenetics can help us to overcome treatment resistance of mental disorders, and possibly detect and prevent th em early.
- Keywords
- léčba, epigenetika, farmakorezistence,
- MeSH
- Alzheimer Disease genetics pathology therapy MeSH
- Cytosine biosynthesis MeSH
- DNA Modification Methylases MeSH
- Mental Disorders * diagnosis drug therapy prevention & control MeSH
- Epigenomics * methods trends MeSH
- Exosomes MeSH
- Gene Expression MeSH
- Histones biosynthesis MeSH
- Clinical Trials as Topic MeSH
- Rats MeSH
- Valproic Acid therapeutic use MeSH
- Drug Resistance MeSH
- Humans MeSH
- Psychopharmacology trends MeSH
- RNA, Long Noncoding history genetics MeSH
- Schizophrenia genetics pathology therapy MeSH
- Synapses physiology drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- MeSH
- 6-Cyano-7-nitroquinoxaline-2,3-dione administration & dosage MeSH
- Receptors, AMPA drug effects MeSH
- Behavior, Animal drug effects MeSH
- Electroencephalography MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Schizophrenia etiology physiopathology MeSH
- Synapses drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
N-methyl-d-aspartate (NMDA) receptors (NMDARs) are highly expressed in the CNS and mediate the slow component of excitatory transmission. The present study was aimed at characterizing the temperature dependence of the kinetic properties of native NMDARs, with special emphasis on the deactivation of synaptic NMDARs. We used patch-clamp recordings to study synaptic NMDARs at layer II/III pyramidal neurons of the rat cortex, recombinant GluN1/GluN2B receptors expressed in human embryonic kidney (HEK293) cells, and NMDARs in cultured hippocampal neurons. We found that time constants characterizing the deactivation of NMDAR-mediated excitatory postsynaptic currents (EPSCs) were similar to those of the deactivation of responses to a brief application of glutamate recorded under conditions of low NMDAR desensitization (whole-cell recording from cultured hippocampal neurons). In contrast, the deactivation of NMDAR-mediated responses exhibiting a high degree of desensitization (outside-out recording) was substantially faster than that of synaptic NMDA receptors. The time constants characterizing the deactivation of synaptic NMDARs and native NMDARs activated by exogenous glutamate application were only weakly temperature sensitive (Q(10)=1.7-2.2), in contrast to those of recombinant GluN1/GluN2B receptors, which are highly temperature sensitive (Q(10)=2.7-3.7). Ifenprodil reduced the amplitude of NMDAR-mediated EPSCs by approximately 50% but had no effect on the time course of deactivation. Analysis of GluN1/GluN2B responses indicated that the double exponential time course of deactivation reflects mainly agonist dissociation and receptor desensitization. We conclude that the temperature dependences of native and recombinant NMDAR are different; in addition, we contribute to a better understanding of the molecular mechanism that controls the time course of NMDAR-mediated EPSCs. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
- MeSH
- Excitatory Amino Acid Antagonists pharmacology MeSH
- Cell Line MeSH
- Excitatory Postsynaptic Potentials physiology drug effects MeSH
- Hippocampus physiology drug effects MeSH
- Kinetics MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Glutamic Acid metabolism MeSH
- Humans MeSH
- Cerebral Cortex physiology drug effects MeSH
- Synaptic Transmission physiology drug effects MeSH
- Piperidines pharmacology MeSH
- Rats, Wistar MeSH
- Pyramidal Cells physiology drug effects MeSH
- Receptors, N-Methyl-D-Aspartate metabolism MeSH
- Synapses physiology drug effects MeSH
- In Vitro Techniques MeSH
- Temperature MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Použili jsme hypotetického modelu založeného na defektivní glutamatergní neurotransmisi způsobené hyperaktivním transportem glutamátu na excitatorických synapsích v prefrontální kůře. Model vysvětluje jak pozitivní, tak negativní symptomy schizofrenie a navíc nabízí alternativní vysvětlení mechanizmu atypických neuroleptik (neuroleptik druhé generace), která jsou účinná při léčbě negativních symptomů. Hypotéza je rovněž v souladu s nedávno publikovanými nálezy zvýšeného transportu glutamátu v prefrontální kůře pacientů se schizofrenií. Mechanizmy, které regulují transport glutamátu, si zaslouží větší pozornost; mohly by být použity při identifikaci nových typů neuroleptik, zaměřených primárně proti negativním symptomům. Laboratorní metody vyvinuté specificky za účelem identifikace takových látek jsou již k dispozici a přinášejí první výsledky.
Hypothetical model based on deficient glutamatergic neurotransmission caused by hyperactive glutamate transport at excitatory synapses in the prefrontal cortex has been used to explain both negative and positive symptoms of schizophrenia. In addition, the model offers an alternative explanation for the mechanizm of actions of neuroleptics, particularly those of second generation (“atypical”) that are successful in treating the negative symptoms. The hypothesis of hyperactive glutamate transport is consistent with recent findings of increased glutamate transport in prefrontal cortex of patients with schizophrenia. It is proposed that mechanizms regulating glutamate transport be used to identify novel classes of neuroleptics targeting primarily negative symptoms. Laboratory techniques developed specifically for the purpose of detecting such compounds are available and have produced first results.
- MeSH
- Nootropic Agents administration & dosage MeSH
- Brain Injuries physiopathology rehabilitation MeSH
- Synapses pathology drug effects MeSH
- Publication type
- Congress MeSH
