OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.
- MeSH
- demence s Lewyho tělísky * diagnostické zobrazování MeSH
- dopamin * metabolismus MeSH
- jednofotonová emisní výpočetní tomografie MeSH
- lidé středního věku MeSH
- lidé MeSH
- Parkinsonova nemoc * diagnostické zobrazování komplikace MeSH
- porucha chování v REM spánku * diagnostické zobrazování MeSH
- presynaptická zakončení metabolismus MeSH
- senioři MeSH
- strojové učení * MeSH
- synukleinopatie * diagnostické zobrazování MeSH
- zobrazení dopaminergního systému MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie 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
- AMPA receptory metabolismus MeSH
- cholesterol farmakologie MeSH
- excitační postsynaptické potenciály účinky léků MeSH
- hipokampus účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- kyselina glutamová metabolismus MeSH
- mozková kůra účinky léků metabolismus MeSH
- nervový přenos * MeSH
- neurony účinky léků metabolismus MeSH
- potkani Wistar MeSH
- presynaptická zakončení účinky léků metabolismus MeSH
- receptory N-methyl-D-aspartátu metabolismus MeSH
- synapse účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Changes in cholesterol concentration in the plasma membrane of presynaptic nerve terminals nonspecifically modulate glutamate transport and homeostasis in the central nervous system. Reduction of the cholesterol content in isolated rat brain nerve terminals (synaptosomes) using cholesterol-depleting agents decreases the glutamate uptake and increases the extracellular level of glutamate in nerve terminals. Extraction of cholesterol from the plasma membrane and its further removal from the synaptosomes by external magnetic field can be achieved by means of magnetic nanoparticles with immobilized cholesterol-depleting agent such as O-methyl-β-cyclodextrin (MCD). A simple approach is developed for preparation of maghemite (γ-Fe2O3) nanoparticles containing chemically bonded MCD. The method is based on preparation of a silanization agent containing MCD. It is synthesized by the reaction of triethoxy(3-isocyanatopropyl)silane with MCD. Base-catalyzed silanization of superparamagnetic γ-Fe2O3 provides a relatively stable colloid product containing 48μmol of MCDg(-1). MCD-modified γ-Fe2O3 nanoparticles decrease the initial rate of the uptake and accumulation of l-[(14)C]glutamate and increase the extracellular l-[(14)C]glutamate level in the preparation of nerve terminals. The effect of MCD-immobilized nanoparticles is the same as that of MCD solution; moreover, magnetic manipulation of the nanoparticles enables removal of bonded cholesterol.
- MeSH
- beta-cyklodextriny chemie farmakologie MeSH
- biologický transport účinky léků MeSH
- buněčná membrána účinky léků metabolismus MeSH
- cholesterol izolace a purifikace metabolismus farmakologie MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- kyselina glutamová metabolismus MeSH
- magnetické nanočástice chemie MeSH
- membránové potenciály účinky léků MeSH
- mozek účinky léků metabolismus MeSH
- potkani Wistar MeSH
- presynaptická zakončení účinky léků metabolismus MeSH
- radioizotopy uhlíku MeSH
- silany chemie MeSH
- synaptozomy účinky léků metabolismus MeSH
- železité sloučeniny chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo compared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured with in vivo microdialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction.SIGNIFICANCE STATEMENT The vulnerability for addiction-like behavior has been associated with psychological traits, such as the propensity to attribute incentive salience to reward cues that is modeled in rats by sign-tracking behavior. Sign-trackers tend to approach and contact cues associated with reward, whereas their counterparts, the goal-trackers, have a preference for approaching the location of the reward. Here, we show that the capacity of presynaptic cholinergic synapses to respond to stimulation by elevating presynaptic choline uptake and releasing acetylcholine is attenuated in sign-trackers. Furthermore, pharmacological inhibition of choline transport induced sign-tracking behavior. Our findings suggest that reduced levels of cholinergic neuromodulation can mediate an attentional bias toward reward-related cues, thereby allowing such cues to exert relatively greater control over behavior.
- MeSH
- acetylcholin metabolismus MeSH
- biologické markery metabolismus MeSH
- cholin metabolismus MeSH
- kauzalita MeSH
- krysa rodu rattus MeSH
- membránové transportní proteiny metabolismus MeSH
- neurony cholinergní fyziologie MeSH
- neurotransmiterové látky metabolismus MeSH
- odklon pozornosti fyziologie MeSH
- odměna * MeSH
- podněty MeSH
- potkani Sprague-Dawley MeSH
- presynaptická zakončení metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Neuronal voltage-gated calcium channels have evolved as one of the most important players for calcium entry into presynaptic endings responsible for the release of neurotransmitters. In turn, and to fine-tune synaptic activity and neuronal communication, numerous neurotransmitters exert a potent negative feedback over the calcium signal provided by G protein-coupled receptors. This regulation pathway of physiologic importance is also extensively exploited for therapeutic purposes, for instance in the treatment of neuropathic pain by morphine and other μ-opioid receptor agonists. However, despite more than three decades of intensive research, important questions remain unsolved regarding the molecular and cellular mechanisms of direct G protein inhibition of voltage-gated calcium channels. In this study, we revisit this particular regulation and explore new considerations.
- MeSH
- blokátory kalciových kanálů farmakologie MeSH
- konformace proteinů MeSH
- lidé MeSH
- neurony metabolismus MeSH
- presynaptická zakončení metabolismus MeSH
- proteiny vázající GTP - beta-podjednotky metabolismus MeSH
- proteiny vázající GTP - gama-podjednotky metabolismus MeSH
- proteiny vázající GTP metabolismus MeSH
- receptory spřažené s G-proteiny metabolismus MeSH
- vápníkové kanály chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The physiological functions of glycine receptors (GlyRs) depend on their subcellular locations. In axonal terminals of the central neurons, GlyRs trigger a slow facilitation of presynaptic transmitter release; however, their spatial relationship to the release sites is not known. In this study, we examined the distribution of GlyRs in the rat glutamatergic calyx of Held nerve terminal using high-resolution pre-embedding immunoelectron microscopy. We performed a quantitative analysis of GlyR-associated immunogold (IG) labeling in 3D reconstructed calyceal segments. A variable density of IG particles and their putative accumulations, inferred from the frequency distribution of inter-IG distances, indicated a non-uniform distribution of the receptors in the calyx. Subsequently, increased densities of IG particles were found in calyceal swellings, structures characterized by extensive exocytosis of glutamate. In swellings as well as in larger calyceal stalks, IG particles did not tend to accumulate near the glutamate releasing zones. On the other hand, GlyRs in swellings (but not in stalks) preferentially occupied membrane regions, unconnected to postsynaptic cells and presumably accessible by ambient glycine. Furthermore, the sites with increased GlyR concentrations were found in swellings tightly juxtaposed with GABA/glycinergic nerve endings. Thus, the results support the concept of an indirect mechanism underlying the modulatory effects of calyceal GlyRs, activated by glycine spillover. We also suggest the existence of an activity-dependent mechanism regulating the surface distribution of α homomeric GlyRs in axonal terminals of central neurons.
- MeSH
- GABA metabolismus MeSH
- glycin metabolismus MeSH
- krysa rodu rattus MeSH
- mozkový kmen cytologie MeSH
- neparametrická statistika MeSH
- neurony cytologie MeSH
- potkani Wistar MeSH
- presynaptická zakončení metabolismus ultrastruktura MeSH
- receptory glycinu metabolismus ultrastruktura MeSH
- synapse metabolismus ultrastruktura MeSH
- techniky in vitro MeSH
- vezikulární transportní protein 1 pro glutamát metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Every cell or neuronal type utilizes its own specific organization of its Ca(2+) homeostasis depending on its specific function and its physiological needs. The magnocellular neurones, with their somata situated in the supraoptic and paraventricular nuclei of the hypothalamus and their nerve terminals populating the posterior hypophysis (neural lobe) are a typical and classical example of a neuroendocrine system, and an important experimental model for attempting to understand the characteristics of the neuronal organization of Ca(2+) homeostasis. The magnocellular neurones synthesize, in a cell specific manner, two neurohormones: arginine-vasopressin (AVP) and oxytocin (OT), which can be released, in a strict Ca(2+)-dependent manner, both at the axonal terminals, in the neural lobe, and at the somatodendritic level. The two types of neurones show also distinct type of bioelectrical activity, associated with specific secretory patterns. In these neurones, the Ca(2+) homeostatic pathways such as the Na(+)/Ca(2+) exchanger (NCX), the endoplasmic reticulum (ER) Ca(2+) pump, the plasmalemmal Ca(2+) pump (PMCA) and the mitochondria are acting in a complementary fashion in clearing Ca(2+) loads that follow neuronal stimulation. The somatodendritic AVP and OT release closely correlates with intracellular Ca(2+) dynamics. More importantly, the ER Ca(2+) stores play a major role in Ca(2+) homeostatic mechanism in identified OT neurones. The balance between the Ca(2+) homeostatic systems that are in the supraoptic neurones differ from those active in the terminals, in which mainly Ca(2+) extrusion through the Ca(2+) pump in the plasma membrane and uptake by mitochondria are active. In both AVP and OT nerve terminals, no functional ER Ca(2+) stores can be evidenced experimentally. We conclude that the physiological significance of the complexity of Ca(2+) homeostatic mechanisms in the somatodendritic region of supraoptic neurones and their terminals can be multifaceted, attributable, in major part, to their specialized electrical activity and Ca(2+)-dependent neurohormone release.
- MeSH
- homeostáza MeSH
- hypofýza fyziologie MeSH
- interakce mezi receptory a ligandy MeSH
- lidé MeSH
- nervová zakončení metabolismus MeSH
- neurosekrece MeSH
- oxytocin metabolismus MeSH
- presynaptická zakončení metabolismus MeSH
- vápníková signalizace MeSH
- vápníkové kanály metabolismus MeSH
- vasopresiny metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
There are two principal mechanisms of acetylcholine (ACh) release from the resting motor nerve terminal: quantal and nonquantal (NQR); the former being only a small fraction of the total, at least at rest. In the present article we summarize basic research about the NQR that is undoubtedly an important trophic factor during endplate development and in adult neuromuscular contacts. NQR helps to eliminate the polyneural innervation of developing muscle fibers, ensures higher excitability of the adult subsynaptic membrane by surplus polarization and protects the RMP from depolarization by regulating the NO cascade and chloride transport. It shortens the endplate potentials by promoting postsynaptic receptor desensitization when AChE is inhibited during anti-AChE poisoning. In adult synapses, it can also activate the electrogenic Na+/K+-pump, change the degree of synchronization of quanta released by the nerve stimulation and affects the contractility of skeletal muscles.
- MeSH
- acetylcholin sekrece MeSH
- chloridy metabolismus MeSH
- excitační postsynaptické potenciály MeSH
- financování organizované MeSH
- kinetika MeSH
- kosterní svaly inervace růst a vývoj MeSH
- lidé MeSH
- modely neurologické MeSH
- motorické neurony sekrece MeSH
- nervosvalové spojení růst a vývoj sekrece MeSH
- nervový přenos MeSH
- oxid dusnatý metabolismus MeSH
- presynaptická zakončení sekrece MeSH
- sodíko-draslíková ATPasa metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
Synaptický aparát, zejména pokud jde o synapsi chemickou, je velmi komplikovaná struktura. Z hlediska tvorby a správné funkce synapse je klíčovou otázkou interakce velkého počtu správně vytvořených proteinů, jak v presynaptickém, tak v postsynaptickém aparátu. Existují údaje o více než 1000 synaptických proteinech v savčích synaptozomech, postsynaptických denzitách a synaptických komplexech. Nicméně je dosud málo známo o buněčných programech, které jsou základem tvorby a funkce synapsí.
Synaptic apparatus is, namely when concerns the chemical synapses, a highly complex structure. The key process of the precise synaptic function appears the interaction of the large number of correctly formed proteins both in the presynaptic and in postsynaptic apparatus. Existing data show more than 1000 of synaptic proteins in the mammalian synaptosomes, presynaptic densities and synaptic complexes. However, very little is known on the cell programs responsible for the development and function of synapses.
- MeSH
- epilepsie patologie MeSH
- finanční podpora výzkumu jako téma MeSH
- histologické techniky metody využití MeSH
- imunohistochemie metody využití MeSH
- lidé MeSH
- mechová vlákna hipokampu anatomie a histologie patologie MeSH
- mozek patologie MeSH
- mozková kůra anatomie a histologie patologie MeSH
- Check Tag
- lidé MeSH
