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Control of Synapse Number by Glia Erik M R EPORTS RGCs (8). Similar results were obtained un- der both conditions. After 2 weeks in culture, Control of Synapse Number we used whole-cell patch-clamp recording to measure the significant enhancement of spon- by Glia taneous synaptic activity by astrocytes (Fig. 1, A and B) (9). In the absence of astroglia, Erik M. Ullian,* Stephanie K. Sapperstein, Karen S. Christopherson, little synaptic activity occurred even when Ben A. Barres RGCs were cultured with their tectal target cells (6). This difference in synaptic activity Although astrocytes constitute nearly half of the cells in our brain, their persisted even after a month in culture, indi- function is a long-standing neurobiological mystery. Here we show by quantal cating that it is not accounted for by a matu- analyses, FM1-43 imaging, immunostaining, and electron microscopy that few rational delay. To examine whether glia reg- synapses form in the absence of glial cells and that the few synapses that do ulate synaptic activity by enhancing postsyn- form are functionally immature. Astrocytes increase the number of mature, aptic responsiveness, we measured the re- functional synapses on central nervous system (CNS) neurons by sevenfold and sponse of RGCs to pulses of L-glutamate are required for synaptic maintenance in vitro. We also show that most syn- applied to the cell somas. Regardless of the apses are generated concurrently with the development of glia in vivo. These presence of glia, RGCs responded with in- data demonstrate a previously unknown function for glia in inducing and ward currents (Fig. 1C) that were blocked by stabilizing CNS synapses, show that CNS synapse number can be profoundly glutamate receptor antagonists (10). The size regulated by nonneuronal signals, and raise the possibility that glia may actively of the postsynaptic response, however, was participate in synaptic plasticity. threefold larger in RGC neurons cultured with glia (Fig. 1D), consistent with the in- Astrocytes, which ensheathe synapses through- rified RGCs in the presence or absence of creased amplitude of spontaneous synaptic out the CNS, are presently thought of as syn- astrocytes. RGCs were cultured for 1 week miniature events (miniature excitatory aptic support cells, clearing ions and neuro- followed by the addition of astrocytes either postsynaptic currents, or mEPSCs) recorded transmitters from the synaptic cleft, but accu- in contact with RGCs or as a feeding layer for in the presence of glia (Fig. 2G). To deter- mulating evidence suggests the possibility of on February 5, 2015 more active roles as well (1–3). The role of glia at CNS synapses has been difficult to study Fig. 1. Glial astrocytes (glia) because glial cells are present in CNS cultures enhance synaptic efficacy by and are often necessary for neuronal survival. In both presynaptic and postsyn- this study, we have taken advantage of recently aptic mechanisms. (A and B)In the absence of glia, only a low developed methods to isolate a defined type of frequency of small spontane- CNS neuron, retinal ganglion cells (RGCs), by ous synaptic currents is ob- immunopanning the cells to greater than 99.5% served (A), whereas in the purity (4, 5) and then culturing them in a de- presence of glia large sponta- www.sciencemag.org fined serum-free medium (5). Using these neous synaptic currents are methods, we have previously shown that RGCs frequently observed (B). All synaptic currents were CNQX- cultured in the presence of astrocyte-condi- sensitive (10). (C) Application tioned medium have 10 times higher levels of of 50-ms pulses of 100 ␮M synaptic activity (6). This glial effect is not L-glutamate to RGC cell bodies simply due to enhancement of RGC maturation, at a holding potential of Ϫ70 because RGCs cultured either in the presence or mV results in sustained inward currents. (D) Current densities absence of glia are electrically excitable, devel- Downloaded from of RGCs cultured in the ab- op comparable numbers of dendrites and axons, sence or presence of glia. and have identical survival rates. In addition, Whole-cell currents: RGCs RGCs cultured under both conditions synthe- without glia, 15.7 Ϯ 4.7 pA/pF; size, secrete, and respond to glutamate (6) and RGCs with glia, 45 Ϯ 8.6 pA/ ϭ express nearly identical levels of mRNAs for a pF (P 0.015, Student’s t large battery of neurotransmitter receptors, volt- test). (E and F) Autaptic EPSCs from RGCs cultured in the ab- age-dependent ion channels, and synaptic pro- sence (E) or presence (F) of teins, as assessed by gene chip analysis (7). In glia. (G and H) Higher synaptic this study, we examine whether the increased failure rates are seen in RGCs synaptic activity in glia is due to an increase in without glia (G) than in RGCs with glia (H). (I) Without glia, the number of synapses or to the efficacy of Ϯ synaptic transmission. 44 18% autaptic neurons have detectable EPSCs, where- To address this question, we cultured pu- as 100% have EPSCS in the presence of glia (Mann-Whit- ney U test, P Ͻ 0.05). (J) Stanford University School of Medicine, Department Quantal content of RGCs cul- of Neurobiology, Fairchild Science Building, Stanford, tured in the absence of glia is CA 94305Ð5125, USA. 7 Ϯ 4 compared with 47 Ϯ 10 *To whom correspondence should be addressed at for RGCs cultured with glia (in- Stanford University School of Medicine, Department cluding failures, P ϭ 0.004). of Neurobiology, Fairchild Science Building, Stanford, Quantal content was deter- CA 94305Ð5125, USA. E-mail: [email protected] mined with the direct method. www.sciencemag.org SCIENCE VOL 291 26 JANUARY 2001 657 R EPORTS mine whether astrocytes also enhanced pre- higher depression rates (Fig. 1, G and H). RGCs that had been cultured with glia (Fig. synaptic function, we measured quantal con- These findings indicate that glia enhance syn- 2A). In both cases, FM1-43 was observed in tent (QC) of evoked responses in autaptic aptic efficacy by both a postsynaptic and a synaptic punctalike spots along dendrites and neurons cultured with a feeding layer of as- presynaptic mechanism. somas (Fig. 2A), and these puncta destained trocytes (Fig. 1, E and F) (11, 12), thus To directly measure presynaptic function with similar kinetics (Fig. 2B). However, glia allowing us to measure presynaptic differenc- without using postsynaptic responsiveness as significantly increased the fluorescence dif- es independently of differences in postsynap- an indicator, we next examined the ability of ference ⌬F, measured from FM1-43–loaded tic responsiveness. Glia increased QC by sev- RGCs to take up the fluorescent stryryl dye puncta before and after destaining, by about enfold (Fig. 1J). In addition, RGCs cultured FM1-43 into synaptic vesicles during activity sevenfold (Fig. 2C). These findings indicate without glia produced EPSCs only half as (13–16). Despite a prolonged depolarization, that glia strongly enhance presynaptic func- often as RGCs cultured with glia (Fig. 1I), RGCs that had been cultured in the absence tion (17). and the EPSCs detected without glia had of glia took up little FM1-43 compared with To determine whether glia enhance pre- synaptic efficacy by increasing calcium in- flux, and thereby triggering synaptic vesicle Fig. 2. Glial astrocytes (glia) in- crease the total number of syn- release (18), we next compared the density of aptic vesicles released. (A to C) voltage-dependent calcium currents in RGCs Labeling of synaptic puncta with cultured in the presence and absence of glia ϩ FM1-43 in high K . In RGCs cul- by measuring whole-cell calcium-current tured in the absence of glia (A, densities at two different holding potentials left), FM1-43 weakly labeled (Ϫ90 and Ϫ50 mV). At both holding poten- puncta; pseudocolor inset shows weakly labeled areas along neu- tials, glia increased calcium current density rites. In RGCs cultured with glia by about two- to threefold (Fig. 2D), suggest- (A, right), FM1-43 strongly la- ing that an increased presynaptic calcium in- beled many puncta. (B) Normal- flux might account for the glial enhancement ized data indicate that puncta of presynaptic function. To test this possibil- destain in the presence or ab- ity directly, we bypassed the endogenous pre- sence of glia with similar time courses. (C) Comparison of the synaptic voltage-gated calcium channels in difference in fluorescence inten- RGCs by using the calcium ionophore iono- sity (⌬F) between fully stained mycin to produce a large presynaptic calcium and fully destained puncta in influx (19, 20). The number of ionomycin- cells cultured with or without induced mEPSCs recorded was still 10-fold glia. RGCs with glia take up sev- greater in RGCs cultured with glia than with- en times more FM1-43: without glia, mean ⌬F ϭ 216 Ϯ 9; with out (Fig. 2, E and F). Comparable results glia, mean ⌬F ϭ 1429 Ϯ 100 for were obtained when 500 mM sucrose or 0.3 RGCs [arbitrary fluorescence nM ␣-latrotoxin were used to trigger vesicu- units, Kruskal-Wallis analysis of lar release rather than ionomycin (10). Simi- variance (ANOVA), P Ͻ 0.001]. ␮ larly, when we used ionomycin to load and Bar, 50 m. (D) RGCs cultured unload presynaptic terminals with FM1-43, with glia display a two- to three- fold increase in Ca2ϩ current vesicular recycling was still greater in RGCs density at a holding potential of cultured with glia (Fig. 2H). Notably, the ⌬F Ϫ90 mV (left). Peak current: values measured with ionomycin in RGCs in Ϫ33.4 pA/pF without glia, Ϫ86.7 the absence of glia were indistinguishable pA/pF with glia. RGCs cultured from the values measured with high-Kϩ stim- with glia display a nearly three- ϩ ulation of these neurons (Fig.
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