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  1. #1
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    Renewed evidence suggests statin/Parkinson's link

    New research showing a strong link between Parkinson's disease and low levels of "bad" cholesterol are so worrying that U.S. researchers are launching a study to look into it.

    The team at the University of North Carolina is planning clinical trials involving thousands of people to see whether statin drugs, which lower low density lipoprotein, or LDL, might actually cause Parkinson's in some people.

    Other research has for several years suggested that people with abnormally low levels of LDL might be at higher risk of Parkinson's.

    Xuemei Huang and colleagues found that patients with low levels of LDL cholesterol are at least three and a half times more likely to develop Parkinson's disease than those with higher LDL levels.

    Writing in the journal Chemistry & Industry, they said they plan a bigger study of patients taking statins, the biggest-selling drugs in the world.

    "I am very concerned, which is why I am planning a 16,000-patient prospective study to examine the possible role of statins," Huang said in a statement.

    Prospective study means the patients are watched for a period of time to see what diseases or conditions develop.

    Huang noted some other studies showed that people with APOE2, a gene that causes naturally low cholesterol, have a higher risk of Parkinson's. Another variation of the gene, APOE4, is associated with a risk of Alzheimer's disease.

    British heart experts expressed alarm about the report and said heart patients should not stop taking statins.

    "We are concerned that any suggestion of a link between statins and Parkinson's disease would unnecessarily scare the millions of people benefiting from statins in the U.K.," said Dr. Peter Weissberg, medical director of the British Heart Foundation.

    "There is no evidence to suggest that statins cause Parkinson's disease. There is, however, overwhelming evidence that statins save lives by preventing heart attacks and strokes."

    Parkinson's is an incurable brain illness that can paralyze patients. Patients may also have difficulty walking and talking and may shake uncontrollably at times.

    According to the National Institutes of Health, Parkinson's affects at least 500,000 people in the United States alone. But heart disease affects 70 million Americans, according to the U.S. Centers for Disease Control and Prevention, and kills more than 910,000 each year.

  2. #2
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    Interesting, but I think the last paragraph highlights the risk factors quite well. I have very low LDL based upon my last lab results (Dec). I wonder if they already have developed a range of relativly healthy LDL--I never thought to ask my Dr.

    Anyone?
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    It would be interesting to read the whole article. As well, I wonder if it is the low LDL levels or some other biological effect that the drug has on the body that is independent of low LDL levels. Correlating low LDL and Parkinson’s may be the same as linking higher ice cream sales to ****.

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    Quote Originally Posted by !!Comatoa$ted
    It would be interesting to read the whole article. As well, I wonder if it is the low LDL levels or some other biological effect that the drug has on the body that is independent of low LDL levels. Correlating low LDL and Parkinson’s may be the same as linking higher ice cream sales to ****.
    Try searching cholesterol and nerve function/development. Many links.

    Then try searching cholesterol levels and depression. Interesting.

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    Quote Originally Posted by ho hum
    Try searching cholesterol and nerve function/development. Many links.

    Then try searching cholesterol levels and depression. Interesting.

    Association such as this are interesting, but I would prefer to understand the causative effects better. Why would a lower LDL be associated with Parkinsons. Does this effect the Swan sheath somehow? Is Cholesterol a substrate in the production of certain nuerotransmitters? If so, does the reduction from a statin effect the production of the transmitter?

    Why would low cholesterol levels (is this total C or a specific fraction thereof?) be associated with depression? Could it be that the chemical changes associated with depression have caused a lowering in the production of Cholesterol?

    These association don't explain a lot.

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    Regarding the Statin/Parkinson correlation: I wonder if the statins, when used to reduce LDL levels to normal, as opposed to below normal, would have the same correlation, and would this show that statins are/aren't responsible for increasing the incidence of Parkinson's?

    The reason that I would like to see the article that is talked about in the OP, is because many times what is reported by the media, and what the article report are 2 different things. I have learned not to trust media reports of studies; I would rather hear it right from the horse’s mouth.

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    Quote Originally Posted by !!Comatoa$ted
    Regarding the Statin/Parkinson correlation: I wonder if the statins, when used to reduce LDL levels to normal, as opposed to below normal, would have the same correlation, and would this show that statins are/aren't responsible for increasing the incidence of Parkinson's?

    The reason that I would like to see the article that is talked about in the OP, is because many times what is reported by the media, and what the article report are 2 different things. I have learned not to trust media reports of studies; I would rather hear it right from the horse’s mouth.

    Even better, I'd like to see the stats collected during the study. It is quite possible to come to more than one conclusion based on the stats and how one wishes to slant the results.

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    Correlation is not causation. And, the six o-clock news is not a peer reviewed journal. Don't listen to the talking head's version of "science." Those people are idiots.

    Just last night I was watching the news, where they were talking about herbal supplements. Their version of a balanced story involved one guy who was selling about book about how herbal supplements are evil, and a person who sells herbal supplements. How in the world is getting the opinions of two biased people with financial ties to their opinions, balanced? They also threw in a sensationalistic story of a woman who burned off her nose with supplements. Here is the article in all its glory.

    http://www.cbsnews.com/stories/2007/...n2359540.shtml

    Not here to debate the merits or lack there of of supplements. Some are good, some are bad, and some are worthless. The point is that the TV news is a horrible place to get a scientific education. Even if you struggle with the concepts or vocabulary, it is worth it to read the original articles in Pubmed.
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    By now even the most reclusive of hermits is probably aware of the link between heart disease and high cholesterol levels. But having too little of the fatlike substance may have its drawbacks, too. Studies suggest that people with low levels of cholesterol are at increased risk for depression.

    Some years ago scientists discovered that people with low cholesterol seem to be more likely to commit suicide. That finding led researchers to wonder if depression might also be connected with cholesterol levels. A 1993 study, in fact, found just such an association, at least for men over age 70. But another group of scientists -- also studying elderly men -- saw no such effect.

    Researchers at the University of Kuwait have linked low cholesterol levels to depression in both men and women, and in all age groups. Studying 100 depressed individuals being treated at Kuwait's only psychiatric hospital, pathologist Samuel Olusi, M.D., and psychiatrist Abdullahi Fido, M.D., found that the patients had lower levels of cholesterol in their blood than did the nondepressed controls. (Incidentally, eating cholesterol-rich foods doesn't raise our cholesterol levels very much; saturated fats, from which our bodies manufacture cholesterol, are a greater contributor to the problem.)

    Because cholesterol may be an important component of brain cell membranes, it's possible that a lack of the substance reduces neurons' ability to process serotonin, the neurotransmitter that helps regulate mood. This malfunction, in turn, could contribute to depression. However, Olusi and Fido note that "our study did not show that lowering serum cholesterol causes depression." It's possible that depression changes a person's eating habits, so that his or her cholesterol levels fall after the illness sets in. The verdict then: The cholesterol-depression link remains intriguing but still not settled.

    http://www.psychologytoday.com/artic...01-000010.html

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    Brain researchers discover bright side of ill-famed molecule
    Nerve cells need cholesterol to establish contacts / New perspectives for the treatment of brain lesions
    A previously unknown role of cholesterol in the formation of contacts between nerve cells has been discovered by researchers at the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany, and at the Centre de Neurochimie in Strasbourg in France (Science, November 09th, 2001). Their results suggest a link between brain cholesterol metabolism and nerve cell development, learning and memory and hint at new strategies to cure injury- or disease-induced brain lesions.

    Brain function depends on the exchange of electrical signals between nerve cells that is mediated by highly specialized contact sites, the socalled synapses. Their formation is a decisive phase during brain development and plays an important role in learning and memory. So far, however, the mechanisms of this process are largely obscure and thus, their elucidation is therefore an important topic of neuroscience research. Moreover, the identification of "synaptogenic" factors is a fundamental prerequisite to repair synaptic connections that have been destroyed by injury, stroke or neurodegenerative diseases like Alzheimer's.

    A clue to the existence of a synaptogenic factor came from a study that Dr. Frank Pfrieger, presently leader of a bilateral research group of the Max-Planck Society and the Centre National de Recherche Scientifique, conducted some years ago in the lab of Prof. B. Barres at Stanford University in the USA. The two researchers examined whether neurons can form contacts by themselves or whether they need help from socalled glial cells. Glial cells form a large part of the brain tissue and support its development and function in many different ways. By studying isolated nerve cells in culture dishes Pfrieger and Barres found that neurons survive and grow under glia-free conditions, but show only few of the electrical signals that are generated by synapses. Soluble factors produced by specific types of glial cells, however, induced a strong potentiation of synaptic activity.

    After his return from the US, Dr. Pfrieger set out to identify the unknown factor and its mode of action with his own research group at the Max-Delbrück-Center for Molecular Medicine in Berlin. Earlier this year, the groups of Pfrieger and Barres showed independently that the glial factor increases the number of synapses and their transmission efficacy. These results indicated that glial cells play indeed a role during synapse development. However, the identity of the synaptogenic factor remained unknown.

    Now, Pfrieger's group achieved the final breakthrough. In the latest issue of Science (November 09th, 2001), they report a surprising result: the long-sought factor turns out to be cholesterol!

    Cholesterol, meanwhile one of the most well-known biological substances, is an essential component of the membrane that surrounds every cell in the body. Its bad reputation stems from the fact that high cholesterol levels in the blood raise the risk for atherosclerosis and consequently heart attack and stroke. The identification of cholesterol as synaptogenic factor shows a surprisingly beneficial side of this infamous molecule. Pfrieger believes that "the availability of cholesterol in the brain may limit the extent of synaptogenesis and that a defective cholesterol metabolism in the brain may therefore impair its development and function".

    Pfrieger's results indicate that nerve cells produce enough cholesterol to survive and to grow, but too little to form enough synaptic contacts. Thus, they depend on external sources of this component. Where does the extra cholesterol come from? Pfrieger remarks that "the brain cannot tap the cholesterol supply in the blood, since the lipoproteins that mediate the transport of cholesterol - including the notorious ldl and hdl - are too big to pass the blood-brain barrier. Therefore, the brain depends on its own cholesterol synthesis."

    According to the new results glial cells produce surplus cholesterol and provide nerve cells with this component. This correlation indicates a new role for glial cells as cholesterol providers and could explain why glial cells secrete cholesterol-rich lipoproteins.

    The new results also raise a series of questions: how does cholesterol promote synaptogenesis? Does it serve as building material for synaptic components or does it act as signal triggering subsequent cellular processes? Do changes in availability of cholesterol in the brain influence mental development, learning or memory? Notably, the results imply a new hypothesis concerning Alzheimer's disease. Structural changes in the socalled apolipoprotein E, a crucial component of cholesterol carrier complexes, raise the risk for an age-dependent form of Alzheimer. This may be due to an impaired supply of nerve cells with cholesterol and thus a reduced turnover of synapses. Pfrieger's group will now address these questions in cooperation with other research teams.

    All in all, the new results throw new light on an often disdained molecule and provide new perspectives for neurobiological research and strategies to cure brain lesions.

    http://www.eurekalert.org/pub_releas...-brd110401.php

  11. #11
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    Here is the report that the previous post was taken from




    PERSPECTIVES: NEUROBIOLOGY

    The smooth operation of the nervous system depends on rapid communication between nerve cells at meeting areas called synapses. Although synapses were first identified 100 years ago, their formation, a process called synaptogenesis, has remained something of a mystery. For example, it is still not clear how many synapses a neuron can make with other nerve cells. Is the number of synapses rigidly preprogrammed or is it plastic, governed by interactions with neighboring cells? Thanks to a simple model system in which a defined type of neuron from the central nervous system is purified and cultured, two intriguing but unanticipated conclusions about synaptogenesis have been reached. The first is that neurons by themselves form few synapses unless they have help from other nerve cells called glial cells [ 1-3]. The second, reported by Mauch et al. [ 4] on page 1354 of this issue, is that the synapse-promoting signal released by glial cells is cholesterol.

    The story begins 4 years ago when Pfrieger and Barres [ 1] asked whether purified retinal ganglion cells would form functional synapses in culture. They obtained these neurons from postnatal rat retinas at a purity of greater than 99.5% with an antibody-selection process called immunopanning [ 5]. They kept their purified retinal ganglion cell cultures alive in a simple serum-free culture medium that prevented most of the cells from undergoing apoptosis despite the absence of a subpopulation of glial cells called astrocytes that secrete factors promoting neuronal survival [ 6]. To their surprise, the retinal ganglion cells exhibited little synaptic activity unless they were cocultured with astrocytes, in which case spontaneous synaptic activity increased 70-fold. To further investigate exactly how these glial cells could so powerfully control synaptic activity in these cultures, the researchers next performed electrophysiology, imaging, immunostaining, and electron microscopy [ 2, 3]. They found that astrocytes increased the total number of synapses on each neuron by sevenfold. Moreover, astrocytes were required to maintain these synapses, because most synapses formed in the presence of astrocytes were quickly lost when these cells were removed [ 2, 7]. These studies suggested that glial cells, long thought to be passive bystanders in the formation and operation of our neural circuitry, might actively participate in the making and breaking of synapses.

    These findings also raised an important question: How do glial cells control the number of synapses? Early work had shown that the astrocyte-derived signal was released into the medium as a soluble protein [ 1]. To identify the signal, Mauch and colleagues fractionated astrocyte-conditioned medium and found an activity with a large molecular weight (150 to 650 kilodaltons) that could bind to heparin [ 4]. They further showed that astrocytes reliably induced the appearance of a protein in neurons, which they identified, by microsequencing and mass spectrometry, as apolipoprotein E (apoE). ApoE is a heparin-binding constituent of the many large lipoprotein particles that transport lipids between cells and around the body. In the brain, apoE is primarily made by astrocytes, and apoE receptors are abundantly expressed by neurons. This suggested to Mauch and co-workers that neurons might take up and accumulate apoE secreted by astrocytes and, thus, that apoE might be the glial-derived synapse-promoting signal they were looking for. Recombinant apoE, however, did not induce the purified neurons to form synapses. Because apoE-containing lipoproteins are cholesterol carriers, the investigators next examined the effects of adding cholesterol to the culture medium. Amazingly, cholesterol by itself induced the neurons to form almost as many synapses as did medium enriched for factors secreted by astrocytes. Moreover, removing cholesterol from this medium or inhibiting cholesterol synthesis abrogated the ability of astrocytes to promote synapse formation. Although the authors did not test whether depletion of apoE from the medium would have a similar effect, they found that a general antagonist of lipoprotein receptors significantly decreased the ability of astrocytes to trigger synapse formation. The simplest explanation for these findings is that cholesterol bound to apoE-containing lipoprotein particles is released by astrocytes and taken up by neurons, where it then promotes an increase in synapse number. Consistent with this possibility, neurons cultured in the presence of astrocytes contain twice as much cholesterol within their membranes as neurons that are cultured alone.

    The new findings raise many important questions. First, is apoE itself the astrocyte-derived protein responsible for increasing synapse number? It remains possible that another apolipoprotein or other yet to-be-identified glial proteins are involved. Second, which of the many low-density lipoprotein (LDL)-related receptor family members that bind to apoE mediate this effect on synapse formation? Although some of these receptors simply aid in the taking up of lipoproteins, others have been implicated in signal transduction [ 8]. This raises the interesting issue of how exactly cholesterol increases synapse formation. One possibility is that cholesterol is needed to activate a signaling pathway that triggers synaptogenesis -- either an apoE receptor pathway or another signaling pathway such as the sonic hedgehog, Wnt, or reelin cascades [ 8, 9]. Alternatively, a sufficient amount of cholesterol itself might be needed to support the structural demands of synaptogenesis. For example, cholesterol binds to several synaptic proteins, and is necessary for the formation of synaptic vesicles and for the clustering of certain postsynaptic receptors [ 10-12].

    But perhaps the most important question is whether the glial delivery of cholesterol to neurons within the brain is the limiting factor regulating synapse formation. Cholesterol within the brain is derived almost entirely through in situ synthesis by brain cells [ 13]. The appearance of most synapses in the developing brain is temporally and spatially coincident with the development of astrocytes, suggesting that synapse formation may depend on astrocyte-derived cholesterol [ 2]. It is possible that once astrocytes begin to develop, neurons always have plenty of cholesterol available to them in vivo. On the other hand, glia have recently been found to control synapse number within the developing cerebellum of transgenic mice whose glia express mutant glutamate receptors [ 14]. These findings are consistent with the possibility that astrocytes, by providing a limiting cholesterol supply to neurons, control synapse formation in vivo.

    Could the cholesterol supply also regulate synaptic plasticity in the adult brain? Although astrocytes are needed to maintain synapses formed in culture, it is not yet clear whether cholesterol is similarly required. The LDL receptor-related protein (LRP), however, has been directly implicated in synaptic plasticity in hippocampal slices [ 15]. Even more intriguing, apoE has long been suspected to be involved in neurodegenerative loss of synaptic plasticity in Alzheimer's disease [ 16]. The apoE4 isoform is associated with an increased risk of late-onset Alzheimer's disease and is less able to promote neurite outgrowth than other apoE isoforms [ 17]. Will apoE4 also differ in its ability to promote synapse formation? Fortunately, identification of cholesterol as the glial-derived synapse-promoting signal should make it possible to investigate the involvement of cholesterol and glia in synaptic development and plasticity in vivo.

    PHOTO (COLOR): Cholesterol -- making a nervous debut. Neurons in culture form few synapses unless glial cells called astrocytes are present. (A) Astrocytes increase synapse number by secreting cholesterol bound to large lipoprotein particles containing apolipoprotein E (apoE). (B) These particles are internalized by neurons, leading to increased cholesterol within neuronal membranes. It is possible that apoE also activates yet to-be-identified signaling pathways within the neurons. (C) These changes stimulate an increase in the number and efficacy of synapses.
    References

    1. F. W. Pfrieger, B. S. Barres, Science 277, 1684 (1997).

    2. E. M. Ullian, S. K. Sapperstein, K. S. Christopherson, B. A. Barres, Science 291, 657 (2001).

    3. K.Nagler, D. Mauch, F. W. Pfrieger, J. Physiol. 533, 665 (2001) [Medline].

    4. D. H. Mauch et al., Science 294, 1354 (2001).

    5. B. A. Barres, B. E. Silverstein, D. P. Corey, L. L. Y. Chun, Neuron 1, 791 (1988) [Medline].

    6. A. Meyer-Franke, M. R. Kaplan, F. W. Pfrieger, B. A. Barres, Neuron 15, 805 (1995) [Medline].

    7. E. Ullian, K. Christopherson, B. Barres, in preparation.

    8. H. Herz, Neuron 29, 571 (2001) [Medline].

    9. D. S. Rice et al., Neuron 31, 929 (2001) [Medline].

    10. A. Thiele, M. J. Hannah, F. Fahrenholz, W. B. Huttner, Nature Cell Biol. 2, 42 (2000) [Medline].

    11. T. Lang et al., EMBO J. 20, 2202 (2001) [Medline].

    12. J. L. Bruses, N. Chauvet, U. Rutishauser, J. Neurosci. 21, 504 (2001) [Medline].

    13. J. M. Dietschy, S. D. Turley, Curr. Opin. Lipidol. 12, 105 (2001) [Medline].

    14. M. Iino et al., Science 292, 926 (2001).

    15. M. Zhuo et al., J. Neurosci. 20, 542 (2000) [Medline].

    16. H. Herz, U. Beffert. Nature Rev. Neurosci. 1, 51 (2000) [Medline].

    17. B. P. Nathan et al., Science 264, 850 (1994) [Medline].

  12. #12
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    Here is the first reference of the above article




    REPORTS

    In the developing nervous system, glial cells guide axons to their target areas, but it is unknown whether they help neurons to establish functional synaptic connections. The role of glial cells in synapse formation and function was studied in cultures of purified neurons from the rat central nervous system. In glia-free cultures, retinal ganglion cells formed synapses with normal ultrastructure but displayed little spontaneous synaptic activity and high failure rates in evoked synaptic transmission. In cocultures with neuroglia, the frequency and amplitude of spontaneous postsynaptic currents were potentiated by 70-fold and 5-fold, respectively, and fewer transmission failures occurred. Glial cells increased the action potential-independent quantal release by 12-fold without affecting neuronal survival. Thus, developing neurons in culture form inefficient synapses that require glial signals to become fully functional.

    Brain development and function depends on glial cells, as they guide the migration of neuronal somata and axons ( 1), promote the survival and differentiation of neurons ( 2), and insulate and nourish neurons ( 3, 4). It is not known, however, whether glial cells also promote the formation and function of synapses, although glial processes ensheath most synapses in the brain ( 4, 5). The recent development of methods to purify ( 6) and culture a specific type of neuron from the central nervous system (CNS) ( 7) has allowed us to investigate whether CNS neurons can form functional synapses in the absence of glial cells.

    We cultured purified postnatal rat retinal ganglion cells (RGCs) without glial cells under serum-free conditions (Fig. 1A) ( 8) that supported neuronal survival (57 +/- 5% of neurons survived after 20 days; mean +/-SEM; n = 3), electrical excitability, and the differentiation of axons and dendrites ( 7). In order to monitor the formation of functional synapses, we recorded spontaneous postsynaptic currents from RGCs (Fig. 1B) ( 9). After 5 days in culture, 50% of the RGCs tested (15 of 31 cells) showed low levels of synaptic activity with excitatory postsynaptic currents (EPSCs) occurring at a mean frequency of 3 +/- 1 min-1 and with a mean peak amplitude of -11 +/- 1 pA (Fig. 2A). After 20 days of culture, 63% of the RGCs tested (n = 24) displayed spontaneous synaptic activity. The frequency and amplitude of the EPSCs had increased to mean values of 18 +/- 7 min-1 and -16 +/- 1 pA (n = 15; Fig. 2A), respectively.

    To study the effect of neuroglia on synapse formation, we cultured RGCs with glial cells from their target region, the superior colliculus ( 10). After 5 days of serum-free culture with glial cells, 90% of the RGCs tested (n = 34) showed spontaneous EPSCs. Coculture with collicular glia increased the mean frequency and the mean amplitude of spontaneous EPSCs to 41 +/- 12 min-1 and -29 +/- 3 pA (n = 30), respectively (Fig. 2A). After 20 days of coculture with glia, every RGC tested (n = 20) showed spontaneous synaptic activity, and the mean EPSC frequency and amplitude were increased to 1265 +/- 212 min-1 and -78 +/- 8 pA, respectively (n = 20; Fig. 2A). A nearly identical glia-induced enhancement of synaptic activity was observed when RGCs were cocultured with their natural synaptic targets, neurons purified from the superficial layers of the superior colliculus ( 11, 12). Thus, collicular glia strongly enhanced the frequency and amplitude of spontaneous EPSCs in cultured RGCs.

    Next, we determined whether glial cells could promote synaptic activity without contacting RGCs. Treatment of RGC cultures with glia-conditioned medium for 10 to 15 days ( 13) increased the frequency and the amplitude of spontaneous EPSCs to 425 +/- 84 min-1 and -31 +/- 2 pA (n = 43), respectively, indicating that a soluble signal from glial cells increased synaptic activity. The glial effect was not mimicked by glutamine ( 8), combinations of various peptide trophic factors, or components of the extracellular matrix, because culturing RGCs for 10 to 15 days with these components did not change the level of synaptic activity compared with control cultures ( 14).

    Because our preparation of collicular glia contained a mixture of cell types, we next examined which type of neuroglia increased the synaptic activity by culturing RGCs for 10 to 15 days with purified astrocytes, oligodendrocytes, or microglial cells ( 15). Both, astrocytes and oligodendrocytes purified from rat optic nerve, increased the frequency and amplitude of spontaneous EPSCs in cultures with (astrocytes, n = 20 neurons; oligodendrocytes, n = 18) or without (astrocytes, n = 20; oligodendrocytes, n = 24, Fig. 2B) direct contact. Collicular microglia did not increase synaptic activity (n = 16). Thus, the ability to potentiate synaptic activity was specific to macroglial cells.

    Glial cells did not enhance the synaptic activity by improving neuronal survival. The percentage of RGCs surviving when cultured above feeding layers of collicular glia or treated with glia-conditioned medium for 10 to 15 days was 107 +/- 5% (n = 6) of the survival rate in glia-free cultures. Furthermore, if glial cells were added to RGCs that were cultured for 10 days without glia, at a time when neuronal survival was stabilized ( 12), the frequency and amplitude of EPSCs were raised within 3 to 4 days to a similar level (386 +/- 91 min-1 and -50 +/- 6 pA, n = 24, two cultures) as in neuron-glia cocultures of comparable age. This confirmed that glial cells increased the synaptic activity independently from neuronal survival.

    Glial cells may have affected neuronal excitability, because in cocultures spontaneous EPSCs often occurred in bursts (Fig. 3A). After 20 days of culture with neuroglia, all neurons tested (n = 20) showed bursts of EPSCs (mean frequency 13 +/- 1 min-1). These bursts were due to action potential-evoked transmitter release, because action potential-independent release occurs randomly ( 16). To test whether neuroglia increased synaptic activity by enhancing neuronal excitability, we blocked action potentials with tetrodotoxin (TTX) and recorded miniature EPSCs (mEPSCs) ( 17). After 12 to 15 days of culture, neuroglia potentiated the mean frequency of mEPSCs by 12-fold from 8 +/-1 min-1 (n = 17) in glia-free cultures to 98 +/- 45 min-1 (n = 15) and increased their amplitudes significantly (P < 0.001; Kolmogorov-Smirnow test; Fig. 3B). The increase in the frequency and amplitude of miniature postsynaptic currents indicated that glial cells acted directly on synapses ( 18).

    Glial cells can potentiate the frequency of quantal synaptic release by enhancing the number or the efficacy of synapses. In order to test whether RGCs formed synapses in the absence of glial cells, we studied 16- to 21-day-old RGC cultures with the electron microscope and identified synapses on the basis of standard ultrastructural criteria ( 19). RGCs formed numerous synaptic contacts when cultured without glial cells and, on average, 2.3 +/- 0.3 (n = 3 cultures) more synapses in the presence of glial cells ( 20). We observed no apparent differences in the synaptic ultrastructure in glia-free cultures and in cocultures (Fig. 3C). In addition, immunofluorescence staining of glia-free and of cocultures demonstrated that RGCs expressed the synaptic vesicle proteins synapsin I, synaptophysin, and synaptotagmin, as judged by punctate-like staining of axons ( 12). Because RGCs formed synaptic contacts in glia-free cultures, the low level of synaptic activity indicated that synapses are inefficient in the absence of glial cells. The twofold increase in the synapse number cannot account for the 12-fold increase in quantal release, suggesting that glial cells enhanced the synaptic efficacy.

    To examine whether glial cells affected synaptic efficacy, we studied evoked synaptic transmission in glia-free and in neuron-glia cocultures ( 21). In 10- to 15-day-old glia-free cultures, extracellular stimulation at 1 Hz evoked EPSCs in only 22% of the RGCs tested (n = 94). In cocultures with glial cells, every RGC (n = 25) showed EPSCs upon extracellular stimulation. In cocultures, the charge transfer of EPSCs evoked at 1 Hz was, on average, four times larger (mean 189 +/- 42 pF; n = 25) than in glia free cultures (44 +/- 6 pF; n = 24). Within a stimulus train, some stimuli failed to induce postsynaptic responses (Fig. 4). In glia-free cultures, the percentage of failures at a stimulation frequency of 1 Hz averaged at 22 +/- 3% (n = 24 neurons). When RGCs were cocultured with glial cells, however, the failure rate was reduced to 2 +/- 1% (n = 25). In both cultures, the failure rate increased with higher stimulation frequencies. In the absence of glial cells, however, this frequency dependence was greater than in the presence of glial cells (Fig. 4A), and at every stimulation frequency tested, the mean failure rates in cocultures were lower than in glia-free cultures (Fig. 4B). If we raised the stimulation frequency from 1 Hz to 5 Hz and 10 Hz, the normalized failure rate ( 21) increased, on average, by 53 +/- 4% and by 83 +/- 4%, respectively, in glia-free cultures (n = 24), but only by 14 +/- 4% and by 44 +/-7%, respectively, in cocultures (n = 24). The differences in failure rates at higher stimulation frequencies cannot be explained by the twofold increase in the number of release sites in cocultures ( 22). In principle, stimulation failures could also be due to unreliable induction or conduction of action potentials. This was unlikely, however, as current-clamp recordings from RGCs ( 21) in glia-free culture (n = 12) showed that antidromic stimulation induced action potentials at every frequency tested. Furthermore, it has been shown previously that failures in synaptic transmission in CNS neurons are caused by the probabilistic nature of transmitter release ( 23). Thus, the observation of frequent stimulation failures in glia-free cultures indicated that the synapses have low efficacies. The higher reliability of synaptic transmission in cocultures indicated that glial cells enhanced the synaptic efficacy.

    In summary, our findings show that the efficient function of developing CNS synapses in vitro depends critically on glial cells, and they raise the question of whether glial cells also regulate synapse function in vivo: Newly formed synapses that are not yet ensheathed by glial cells may be inefficient. Moreover, the efficacy of adult synapses may also depend on their intimate partnership with glial cells ( 24).



    GRAPHS: Fig. 1. Spontaneous synaptic activity in purified RGCs that were cultured for 5 days in defined, serum-free medium in the absence (left) or presence (right) of collicular glia. (A) Hoffmann-modulation contrast micrographs of RGCs. Scale bar, 50 Mu m. The density of neurons was similar in both cultures. (B) Whole-cell patch-clamp recordings of spontaneous EPSCs from RGCs at a holding potential of -70 mV.

    GRAPHS: Fig. 2. Glial cells potentiated synaptic activity in cultured RGCs. (A) Frequency and mean peak amplitude are shown for spontaneous EPSCs recorded from RGCs that were cultured for 5 (left) or 20 days (right) without (shaded square) and with (square) collicular glia. Each square represents the synaptic activity in each neuron, tested with the EPSC frequency plotted against the mean EPSC amplitude. (B) The effects of different glial cell types on spontaneous synaptic activity are shown. Astrocytes and oligodendrocytes, but not collicular microglia, potentiated the frequency and amplitude of EPSCs (left). The effect did not require direct contact to neurons, as feeding layers of mixed collicular glia, astrocytes, or oligodendrocytes potentiated synaptic activity in RGCs (right). Before the recordings, RGCs were cultured for 10 to 15 days with different glial cell types in serum-free medium ( 15). Averaged EPSC frequencies of all neurons from each culture were plotted against the mean EPSC peak amplitudes. Error bars indicate SEM.

    GRAPHS: Fig. 3. (A) Bursts of spontaneous synaptic activity occurred frequently in RGCs that were cocultured with glial cells (right) but never in glia-free cultures (left). (B) Glial cells increased the frequency and amplitude of action potential-independent mEPSCs in 12- to 15-day-old cultures ( 17). Cumulative frequency distribution of mEPSC frequencies (left) in RGC cultures without (thick line) and with (thin line) collicular glia. Amplitude histograms (right) of mEPSCs (filled bars) and recording noise (open bars) in the absence (upper panel) and presence (lower panel) of collicular glia. Cumul. frequency, cumulative frequency; Rel. Freq., relative frequency. (C) Electron micrographs of synapses formed by RGCs that were cultured for 20 days in the absence (left) and presence (right) of glial cells. Scale bars, 0.3 Mu m.

    GRAPHS: Fig. 4. Glial cells decreased the failure rate of evoked synaptic transmission. (A) In glia-free cultures, the failure rate increased steeply with the stimulation frequency, whereas in the presence of glial cells, synapses could sustain high transmission frequencies. EPSCs were evoked by extracellular stimulation in RGCs cultured for 15 days in the absence (upper panel) or presence (lower panel) of collicular glia. For each RGC, four stimulus trains were applied at the indicated frequencies. The failure rates are indicated. (B) Glial cells decreased the failure rate at every stimulation frequency tested. The failure rates averaged from all neurons tested were plotted against the stimulation frequency. Error bars indicate SEM. RGCs were cultured for 10 to 15 days without (shaded square) and with (square) collicular glia. The inset shows an EPSC evoked by extracellular stimulation (left trace) and a stimulation failure (right trace). The membrane potential was held at -70 mV; scale bars indicate 60 pA and 3 ms.
    Last edited by !!Comatoa$ted; 01-16-07 at 07:37 PM.

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    Quote Originally Posted by ho hum
    The team ... is planning clinical trials ... to see whether statin drugs ... might actually cause Parkinson's in some people.
    Poor reporting, or poor summarizing. They are looking at a possible statistical correlation, not at a possible "cause". The two are quite different.

    There are several statistical correlations with Parkinson's, for instance, people who live on farms have a significantly higher incidence than the general population. Why? Much research later: no idea.

    If it is shown that people with low LDL have a significantly higher incidence than the general population, we will still know next to nothing about (non-trauma) causes of Parkinson's disease. This is nothing to get excited about.
    Stupidity got us into this mess - why can't it get us out?

    - Will Rogers

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