CNS Synaptogenesis Promoted by Glia-Derived Cholesterol

Mauch, Daniela H.; Nägler, Karl; Schumacher, Stefan; Göritz, Christian; Müller, Eva‐Christina; Otto, Albrecht; Pfrieger, Frank W.

doi:10.1126/science.294.5545.1354

Cited by 1,480 publications

(1,217 citation statements)

References 29 publications

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“…Higher neuron densities that we observed in association with added astroglia are likely to result from this decreased excitotoxicity and from trophic factors that are released by astroglia and promote neuronal survival. Mauch et al (2001) showed that cholesterol produced by astroglia added to cultures of retinal ganglion neurons contributes to an increased quantal content, a higher density of synapsin puncta, an increased EPSC frequency and a decrease failure rate at synapses. Thrombospondin, an extracellular matrix protein, is another neurotrophic factor released by astroglia that promotes synaptogenesis (Christopherson et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Added astroglia promote greater synapse density and higher activity in neuronal networks

2007

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Astroglia are known to potentiate individual synapses, but their contribution to networks is unclear.Here we examined the effect of adding either astroglia or media conditioned by astroglia on entire networks of rat hippocampal neurons cultured on microelectrode arrays. Added astroglia increased spontaneous spike rates nearly two-fold and glutamate-stimulated spiking by six-fold, with desensitization eliminated for bath addition of 25 μM glutamate. Astrocyte-conditioned medium partly mimicked the effects of added astroglia. Bursting behavior was largely unaffected by added astroglia except with added glutamate. Addition of the GABA A receptor antagonist bicuculline also increased spike rates but with more subtle differences between networks without or with added astroglia. This indicates that networks without added astroglia were inhibited greatly. In all conditions, the log-log distribution of spike rates fit well to linear distributions over three orders of magnitude. Networks with added astroglia shifted consistently toward higher spike rates. Immunostaining for GFAP revealed a linear increase with added astroglia, which also increased neuronal survival. The increased spike rates with added astroglia correlated with a 1.7-fold increase in immunoreactive synaptophysin puncta, and increases of six-fold for GABA Aβ , two-fold for NMDA-R1 and two-fold for Glu-R1 puncta, with receptor clustering that indicated synaptic scaling. Together, these results indicate that added astroglia increase the density of synapses and receptors, and facilitate higher spike rates for many elements in the network. These effects are reproduced by glia-conditioned media, with the exception of glutamate-mediated transmission.

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Section: Discussionmentioning

confidence: 99%

Added astroglia promote greater synapse density and higher activity in neuronal networks

2007

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“…Astrocytes also increase the number of functional synapses on CNS neurons sevenfold, and are required for maintenance of synapses in vitro (Ullian et al, 2001). Further experiments show that cholesterol derived from CNS glia is sufficient to facilitate synapse formation (Mauch et al, 2001). These studies suggest that glia may dynamically regulate synapse number.…”

Section: Glia-another Source Of Extrinsic Regulatory Signalsmentioning

confidence: 99%

Regulatory mechanisms that govern nicotinic synapse formation in neurons

et al. 2002

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Individual cholinoceptive neurons express high levels of different neuronal nicotinic acetylcholine receptor (nAChR) subtypes, and target them to the appropriate synaptic regions for proper function. This review focuses on the intercellular and intracellular processes that regulate nAChR expression in vertebrate peripheral nervous system (PNS) and central nervous system (CNS) neurons. Specifically, we discuss the cellular and molecular mechanisms that govern the induction and maintenance of nAChR expression-innervation, target tissue interactions, soluble factors, and activity. We define the regulatory principles of interneuronal nicotinic synapse differentiation that have emerged from these studies. We also discuss the molecular players that target nAChRs to the surface membrane and the interneuronal synapse.

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“…It is a major structural component of plasma membranes and myelin, where it is critical for rapid conduction of nerve transmission. Cholesterol has also been directly implicated in various neuronal functions, including synaptogenesis and neurotransmitter release (Mauch et al, 2001 andThiele et al, 2000). Indirectly it has a general influence on cerebral biochemistry via conversion into bioactive steroids such as neurosteroids and oxysterols.…”

Section: Introductionmentioning

confidence: 99%

Bi-lateral changes to hippocampal cholesterol levels during epileptogenesis and in chronic epilepsy following focal-onset status epilepticus in mice

Heverin

Engel

Meaney³

et al. 2012

Brain Research

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Brain cholesterol homeostasis has been shown to be disrupted in neurodegenerative conditions such as Alzheimer's and Huntington's diseases. Investigations in animal models of seizure--induced brain injury suggest that brain cholesterol levels are altered by prolonged seizures (status epilepticus) and are a feature of the pathophysiology of temporal lobe epilepsy. The present study measured hippocampal sterol levels in a model of unilateral hippocampal injury triggered by focal--onset status epilepticus, and in chronically epileptic mice. Status epilepticus was induced by intra--amygdala microinjection of kainic acid and ipsilateral and contralateral hippocampus analyzed. No significant changes were found for ipsilateral or contralateral hippocampal levels of desmosterol or lathosterol at any time after SE as measured by gas chromatographymass spectrometry. 24S--hydroxycholesterol and cholesterol levels were unchanged up to 24 h after status epilepticus but were decreased in the ipsilateral hippocampus during early epileptogenesis and in chronically epileptic mice. Levels of cholesterol were also reduced in the contralateral hippocampus during epileptogenesis and in chronic epileptic mice. Treatment of mice with the anti--inflammatory cholesterol synthesis inhibitor lovastatin did not alter seizures during status epilepticus or seizure--induced neuronal death. Thus, changes to hippocampal cholesterol homeostasis predominantly begin during epileptogenesis, occur bi--laterally even when the initial precipitating injury is unilateral, and continue into the chronic epileptic period.

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CNS Synaptogenesis Promoted by Glia-Derived Cholesterol

Cited by 1,480 publications

References 29 publications

Added astroglia promote greater synapse density and higher activity in neuronal networks

Added astroglia promote greater synapse density and higher activity in neuronal networks

Regulatory mechanisms that govern nicotinic synapse formation in neurons

Bi-lateral changes to hippocampal cholesterol levels during epileptogenesis and in chronic epilepsy following focal-onset status epilepticus in mice

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