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The Journal of Neuroscience, August 15, 1999, 19(16):6897-6906
Three-Dimensional Relationships between Hippocampal Synapses
and Astrocytes
Rachel
Ventura1 and
Kristen M.
Harris2
1 Harvard College and 2 Program in
Neuroscience, Harvard Medical School, Division of Neuroscience in the
Department of Neurology, Children's Hospital, Boston, Massachusetts
02115
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ABSTRACT |
Recent studies show that glutamate transporter-mediated currents
occur in astrocytes when glutamate is released from hippocampal synapses. These transporters remove excess glutamate from the extracellular space, thereby facilitating synaptic input specificity and preventing neurotoxicity. Little is known about the position of
astrocytic processes at hippocampal synapses. Serial electron microscopy and three-dimensional analyses were used to investigate structural relationships between astrocytes and synapses in stratum radiatum of hippocampal area CA1 in the mature rat in
vivo and in slices. Only 57 ± 11% of the synapses had
astrocytic processes apposed to them. Of these, the astrocytic
processes surrounded less than half (0.43 ± 22) of the synaptic
interface. Other studies suggest that astrocytes extend processes
toward higher concentrations of glutamate; thus the presence of
astrocytic processes at particular hippocampal synapses might signal
which ones are releasing glutamate. The distance between nearest
neighboring synapses was usually (~95%) <1 µm. Astrocytic
processes occurred along the extracellular path between 33% of the
neighboring synapses, neuronal processes occurred along the path
between another 66% of the neighboring synapses, and only 1% of the
synapses were close enough such that neither astrocytic nor neuronal
processes occurred between them. These morphological arrangements
suggest that the glutamate released at approximately two-thirds of
hippocampal synapses might diffuse to other synapses, unless neuronal
glutamate transporters are more effective than previously reported. The
findings also suggest that physiological recordings made from
hippocampal astrocytes do not uniformly sample the glutamate released
from all hippocampal synapses.
Key words:
Key words: astrocytes; serial electron microscopy; glutamate spillover; transporters; long-term potentiation; multiple
synapse boutons
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INTRODUCTION |
The location and distribution of
astrocytic processes is important for regulating the extracellular
milieu in the CNS. Astrocytes provide energy for neuronal function and
modulate the formation and efficacy of synapses (Pfrieger and Barres,
1996 , 1997; Laming et al., 1998; Smith, 1998). They regulate
extracellular glutamate, via glutamate transporters (Rothstein et al.,
1994; Chaudhry et al., 1995), and recycle glutamate via glutamine and
intermediates of the tricarboxylic acid cycle (Schousboe et al., 1997;
Sonnewald et al., 1997). By clearing excess glutamate from the
extracellular space (ECS), astrocytes protect against excitotoxic
glutamate concentrations that can lead to neuronal cell death (Choi,
1988; Rosenberg and Aizenman, 1989; Rosenberg et al., 1992; Mennerick et al., 1996; Rothstein et al., 1996; Porter and McCarthy, 1997). Astrocytes are also likely to communicate directly with neurons via
cell-cell adhesion junctions (Spacek and Harris, 1998) and intercellular calcium signaling (Parpura et al., 1994; Porter and
McCarthy, 1996; Verkhratsky and Kettenmann, 1996; Vernadakis, 1996).
Glia occupy ~50% of the total brain volume (Peters et al., 1991;
Laming et al., 1998). However, glial processes are not uniformly distributed in different brain regions. In the cerebellar cortex, nearly all of the parallel and climbing fiber synapses are completely ensheathed by processes of the Bergmann glia (Spacek, 1985).
Physiological recordings show that these glia are responsive to
glutamate released at the synapses (Bergles et al., 1997; Linden, 1997)
and that the glial transporter-mediated currents potentiate in parallel with long-term potentiation (LTP) at the synapses (Linden, 1997, 1998).
In contrast, only 29% of neocortical synapses are contacted by
astrocytes, and these are not fully surrounded by the astrocytic processes (Spacek, 1985). Furthermore, the structural relationships between astrocytes and synapses can change during development, in
response to exogeneously applied glutamate, and with altered neuronal
function (Pomeroy and Purves, 1988; Cornell-Bell et al., 1990; Sirevaag
and Greenough, 1991; Harris and Rosenberg, 1993; Hawrylak et al., 1993;
Anderson et al., 1994; Jones and Greenough, 1996; Theodosis and
MacVicar, 1996).
Recent whole-cell recordings from astrocytes show glutamate transporter
currents in response to glutamate released at hippocampal CA1 synapses
(Bergles and Jahr, 1997). These transporter currents are potentiated
for a few minutes during post-tetanic potentiation, but not during LTP
of the hippocampal synapses (Diamond et al., 1998; Luscher et al.,
1998), in contrast with the cerebellar Bergmann glia. Other studies in
hippocampus suggest that glutamate released at one synapse might
diffuse to neighboring synapses (Harris, 1995; Kullmann et al., 1996;
Barbour and Hausser, 1997; Engert and Bonhoeffer, 1997; Malenka and
Nicoll, 1997; Kullmann and Asztely, 1998). This "glutamate
spillover" could facilitate synchronization of synaptic inputs but
also could reduce synaptic input specificity.
Here serial electron microscopy (EM) and three-dimensional (3D)
analyses were used to determine the structural features of hippocampal
synapses and neighboring astrocytic processes that might regulate
glutamate. In addition, the distance of the extracellular path between
neighboring synapses was measured, and the structural components along
the path that might affect the diffusion of glutamate were delineated.
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MATERIALS AND METHODS |
All of our protocols undergo yearly review by the Animal Care
and Use Committee at Children's Hospital according to the National Institutes of Health guidelines. EM series from previous studies were
used. Some were from the hippocampi of two male rats (rat 1, 137 gm,
39 d; rat 2, 310 gm, 77 d), which were prepared under deep
pentobarbital anesthesia by intravascular perfusion with 2.5%
glutaraldehyde, 2% paraformaldehyde, 1 mM
CaCl2, and 2 mM MgCl2 at pH 7.4, 40-45°C, and 4 psi pressure
(Harris and Stevens, 1989; Harris et al., 1992). Other series were from
hippocampal slices from two male rats (rat 3, 326 gm, 53 d; rat 4, 279 gm, 60 d), which had been prepared by microwave-enhanced
fixation (Sorra and Harris, 1998). All of the series were located
150-250 µm from the hippocampal CA1 pyramidal cell body layer in the
middle of stratum radiatum.
Table 1 summarizes the sources of each sample used for the analyses
described in Results. The first two samples of rat 1 were used in all
of the analyses. The other samples were used to assess the generality
of the results in different animals, as well as in hippocampal slices
maintained in vitro.
New 3D reconstructions were completed using software programs developed
in the Image Graphics Laboratory at Children's Hospital [available
through http://synapses.tch.harvard.edu (until October, 1999) and
http://www.nimh.nih.gov/neuroinformatics/]. Photographs from serial
sections were scanned using the HP Scanjet 4C scanner, and then the
images were digitally rotated and adjusted in the x-y plane to obtain
optimal alignment. Traces were superimposed on objects of interest and
volumetric, areal, or linear dimensions were computed via calibrated
pixels as determined by a calibration grid (Ted Pella, Inc., Redding,
CA) that was originally photographed and then scanned with
each series. 3D surfaces were rendered using 3D Studio Max (Kinetix,
San Francisco, CA).
Statistics were performed using SigmaStat (Jandel Scientific), and all
data are represented either as the individual sample points distributed
around the mean or as the mean ± SD, depending on the specific
analysis described in Results.
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RESULTS |
Astrocytic content in stratum radiatum of hippocampal area CA1
Astrocytic processes were identified by their irregular, stellate
shape and by the presence of glycogen granules and bundles of
intermediate filaments (data not shown) in a relatively clear cytoplasm
(Fig. 1a) (also see Peters et
al., 1991). Astrocytic content in the neuropil of stratum radiatum was
estimated from 23 randomly selected sections obtained from each of the
four rats (analysis 1, Table 1). The
astrocytic content was determined by outlining and computing the area
of all astrocytic profiles and dividing by the total area on each
section. Fifteen of these sections had only astrocytic processes, which
occupied 4 ± 1% of the total area. Eight samples also had a
portion of an astrocytic cell body, which together with the astrocytic
processes occupied 7 ± 2% of the total area.
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Figure 1.
Astrocytic profiles and 3D reconstructions
illustrating their relationships to synapses in the middle of stratum
radiatum of hippocampal area CA1. a, Astrocytic profiles
are illustrated (blue) on a single thin section in the
vicinity of 11 synapses (arrows). The identity of each
of the astrocytic profiles occurring on this single EM section was
confirmed by viewing serial sections. On this one section, three
synapses have astrocytic profiles at their perimeters
(arrowheads). To identify whether astrocytic processes
occurred at the perimeter of the other synapses, they were viewed
through serial sections, and four more of the synapses were found to
have astrocytic profiles at their perimeters, for a total of seven.
b-d, 3D reconstructions illustrate astrocytic profiles
(blue), boutons (green), spines
(gray), and PSDs (red). Astrocytic
profiles surround (b) 50% of the perimeter of
this macular synapse and (c) 3% of the perimeter
of a perforated synapse, both occurring on SSBs. In d,
three synapses occur with a single presynaptic bouton, called a
multiple synapse bouton, and a single astrocytic process
surrounds 75, 64, or 100% of the perimeter of each synapse from
left to right, respectively. Scale bars:
1 µm (shown in b for b-d).
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3D reconstructions of synaptic complexes including
astrocytic profiles
Twenty-three representative synapses from rats 1 and 2 were
selected for complete 3D reconstruction of the synaptic complexes including the presynaptic bouton, postsynaptic spine, and associated astrocytic processes (Fig. 1b-d, Table 1). The synaptic
complexes had postsynaptic densities (PSDs) with continuous
"macular" (Fig. 1b) shapes or with regions that were
"perforated" by electron lucent areas (Fig. 1c). Both
single synapse boutons (SSBs) (Figs. 1b,c) and multiple
synapse boutons (MSBs) (Fig. 1d) were present. The synaptic
complexes occupied from 0.5 to 1.2 µm3.
The axon-spine interface
The axon-spine interfaces have both synaptic and nonsynaptic
components. The synaptic interface has a widened synaptic cleft bordered by vesicles in the presynaptic axonal bouton and a PSD in the
dendritic spine (Fig. 2a). The
nonsynaptic interface has a thin extracellular space bordered by spine
and bouton membranes without specialization (Fig. 2a). The
nonsynaptic interface may also contain molecules important for synaptic
function, such as those involved in endocytosis or glutamate transport.
The perimeter of the axon-spine interface is where substances secreted
into the synaptic cleft might escape and diffuse to neighboring
synapses.
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Figure 2.
The axon-spine interface.
a, Schematic illustration of the PSD, the nonsynaptic
interface, and the perimeter of the axon-spine interface viewed
en face. b, Five 3D reconstructions of
the axon-spine interface arranged clockwise in order of increasing PSD
size. These reconstructions demonstrate the variability in the sizes
and shape of the PSDs and the nonsynaptic interfaces. Scale bar: 1 µm. c, Larger synapses have larger nonsynaptic
interfaces as well.
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The total area of the axon-spine interface was measured by 3D
reconstruction for 187 synapses from rats 1 and 2 (Table 1). The
synaptic interface was determined by measuring the area of the PSD. The
difference between the total area of the axon-spine interface and the
area of the PSD equaled the nonsynaptic interface area. The areas of
the synaptic and nonsynaptic interfaces scaled proportionately (Fig.
2b,c) (r = 0.66). The axon-spine interface of the macular synapses ranged from 0.02 to 0.23 µm2 and had 48 ± 1% nonsynaptic
interface. In contrast, the axon-spine interface of the perforated
synapses ranged from 0.25 to 1.1 µm2 and
had 63 ± 2% nonsynaptic interface (Mann-Whitney rank sum test,
t = 2167; p < 0.001). The volumes of
the synaptic clefts were estimated by multiplying the interface area
times cleft width for representative small and large synapses. The
volume of the synaptic cleft ranged from 0.15 × 10 3 to 2.1 × 103
µm3 at macular synapses, and 1.7 × 103 to 7.6 × 103
µm3 at the perforated synapses. The
volume of the nonsynaptic interface ranged from 0.005 × 103 to 3.5 × 103
µm3 at the macular synapses and 2.1 × 103 to 17 × 103
µm3 at the perforated synapses.
Astrocytes at the perimeter of the axon-spine interface
Astrocytes surrounding the perimeter of the axon-spine interface
are ideally situated to regulate glutamate and other substances released at synapses. To determine what percentage of hippocampal synapses had astrocytes at their perimeter, all complete synaptic complexes within the series from rats 1 and 3 were analyzed (Fig. 3, Table 1). Because the sample volumes
were substantially larger (21-130 µm3) (Table 1)
than the largest synaptic complex (1.2 µm3, see above), these volumetric
analyses contained representative sizes and types of synapses. There
were 229 complete synaptic complexes in these sample volumes. Of these,
197 had macular and 32 had perforated PSDs, and 187 occurred on SSBs
and 42 occurred on MSBs. Astrocytic profiles occurred at the perimeter
of the axon-spine interface of 57% of the synapses (Fig. 3); 44%
were astrocytic processes, and 13% were astrocytic cell bodies.
Astrocytes occurred at 52% of the macular synapses, at 88% of the
perforated synapses, at 61% of the SSBs, and at 40% of the MSBs (Fig.
3).
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Figure 3.
Percentage of synapses with astrocytic profiles at
the perimeter of the axon-spine interface. (Height of bar = the mean
across 4 series volumes; individual values are superimposed; total
n = 229 synapses.)
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The 3D reconstructions illustrate a high variation in how much of
the perimeter of the axon-spine interface was surrounded by
astrocytic profiles (Fig. 1). The following procedure was used to
estimate the fraction of this perimeter that was surrounded for the 131 synapses with astrocytic profiles. On each section of a cross-sectioned synapse, the perimeter had two parts, one at each
edge of the axon-spine interface. When the cap (i.e., the last
section) of the axon-spine interface was reached, the next section was
evaluated to determine whether astrocytic processes surrounded the cap.
Then the fraction of edges with an astrocytic profile was determined.
The fraction of this perimeter that was surrounded by astrocytic
profiles was 0.43 ± 0.22 (Fig.
4). At macular synapses the fraction that
was surrounded was 0.47 ± 0.23 compared with 0.34 ± 0.19 at perforated synapses (t = 2.678;
p < 0.01). The degree to which the astrocytic profiles
surrounded synapses on SSBs (0.45 ± 0.23, n = 114) versus MSBs (0.38 ± 0.20, n = 17) was not
significantly different (t = 1.121; p = 0.264). There tended to be more astrocytic coverage at synapses with a smaller nonsynaptic interface, although this trend did not reach statistical significance (r =  0.12, p = 0.09).
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Figure 4.
Fraction of the perimeter of individual
hippocampal synapses that is surrounded by astrocytic profiles
(mean ± SD; n = 131 synapses). The amount of
astrocyte surrounding the perimeter at macular synapses
(n = 103) was greater than at perforated synapses
(n = 28; *p < 0.01). None of
the other differences reached statistical significance.
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Distance and composition of the path between nearest
neighboring synapses
If glutamate or other substances escape from the synaptic cleft,
their impact on neighboring synapses would be affected by the distance
they must diffuse. In addition the occurrence of astrocytic or neuronal
processes along the path might impede diffusion structurally or via
binding and subsequent transport. The nearest neighboring (NN) synapse
could be identified for 141 of the synapses from rat 1 (Table 1). The
NN synapse was found either on the same section (n = 98), as is shown in Figure 5, or at an
angle through adjacent serial sections (n = 43). The
length of the tortuous path through extracellular space was measured
between neighboring synapses. When the path traversed more than one
section, the Pythagorean theorem [c = sqrt
(a2 + b2)] was applied. The length
across adjacent sections (c) was computed by measuring the
linear displacement (a) and then counting the number of
sections traversed and multiplying by section thickness (b).
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Figure 5.
Five pairs of nearest neighboring
(NN) synapses. EM (a) and
schematic (b) illustrations of the extracellular
path among a cluster of neighboring synapses that have neuronal
(N, dotted) processes or neuronal
membranes of the axon-spine interface between them. NN path lengths
(gray) denoted by double arrows
signify mutual NN paths, whereas those with single
arrows signify one-way NN paths. Path lengths in
b from left to right are
0.85, 0.47, and 0.15 µm. c, d, EM and
schematic representation of NN synapses that have both neuronal and
astrocytic (A, striped) profiles along
that path between them, which is 1.1 µm. In e and
f, the two synapses are immediately adjacent to one
another with almost no distance (<0.01 µm) between them. In this
case, the two NN synapses are on an MSB; in the only other case where
synapses were this close to one another, the NN synapses were on two
different boutons. Scale bar (shown in b): a,
b, 1 µm; (shown in d) c-f, 1 µm.
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The path between NN synapses often had neuronal (Fig. 5a,b)
and/or astrocytic profiles between them (Fig. 5c,d). Only
rarely were the synapses so close to one another that neither neuronal nor astrocytic profiles separated them (Fig. 5e,f).
The NN synapse occurred either on the same bouton (Fig. 5b,
NN1 2) or on a different bouton (Fig. 5b,
NN23). Although 22% of the synapses occurred on MSBs
(Fig. 6a), most of them had NN
synapses on a different bouton (Fig. 6b). Overall, 88% of
the NN synapses occurred on different presynaptic boutons; thus
substances escaping from their axon-spine interfaces could reduce
input specificity.
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Figure 6.
Percentage of synapses on SSBs and MSBs.
a, Of the 229 synapses evaluated, 187 were on SSBs and
42 were on MSBs. b, Only 32 of the synapses on MSBs had
the NNs within the series volume: 14 had their NN on the same MSB,
whereas 18 had their NNs on a different bouton.
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Neurotransmitter can be released at the edge and the center of the
synaptic interface; hence both edge-to-edge and center-to-center distances are relevant for understanding diffusion between synapses. The shortest distances through extracellular space between the edges of
the PSDs on NN synapses were measured. Then the additional distance
from the center to the edge of the synapse was computed by measuring
the total PSD area and calculating the average radius, as though the
PSD were circular. These radii were added to the edge-to-edge distances
to yield the approximate center-to-center distances between NN
synapses. The distances between edges of NN synapses ranged from 0.063 to 1.4 µm, with a mean of 0.42 ± 0.2 µm. The distances
between the calculated centers of synapses ranged from 0.26 to 1.8 µm, with a mean of 0.65 ± 0.3 µm (Fig. 7a).
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Figure 7.
Distances and composition of processes along the
paths between NN synapses. a, These measurements were
obtained for 141 synapses. The mean edge-to-edge path length was
0.42 ± 0.2 µm, and the mean center-to-center path length was
0.65 ± 0.3 µm. b, Of these, the path between 48 NN synapses had both astrocytic and neuronal membrane along it, whereas
91 had neuronal but no astrocytic membrane; only two pairs of NN
synapses had neither astrocytic nor neuronal membrane between
them.
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Approximately 33% of the NN synapse pairs had an astrocytic profile
somewhere along the shortest path between them (Fig. 7b). Another 65% had neuronal membranes and processes between them, whereas
<1.5% of the synapses had neither astrocytic nor neuronal membrane
between them. Distances between nearest neighboring synapses were
longer when astrocytes occurred along the path (0.53 ± 0.24; n = 48) than when they did not (0.36 ± 0.19;
n = 93; Mann Whitney rank sum test, t = 4481; p < 0.001).
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DISCUSSION |
The focus of this work has been to delineate which variations in
the structural features of hippocampal spine synapses and their
associated astrocytic processes might influence the regulation of
glutamate. The results show that there is large variation in the
composition of the axon-spine interface, in whether astrocytic processes surround this interface, and in whether astrocytic or neuronal processes occur along the path between neighboring synapses. This variation in structure suggests that glutamate escapes
nonuniformly from hippocampal synapses and that astrocytes regulate
these synapses unequally.
Thin sheets of astrocytic processes intermingle with dendrites, axons,
and synapses, and occupy only ~5% of the neuropil in stratum
radiatum of area CA1. This 5% value compares well with stereological
measurements in area CA1 and neocortex (Hawrylak et al., 1993; Jones,
Greenough, 1996) but contrasts with cerebellar cortex (Palay and
Chan-Palay, 1974). Other studies show that ~10% of all cell
membranes in hippocampus are astrocytic, contrasting with ~27% in
cerebellar cortex (Lehre and Danbolt, 1998).
The disposition of astrocytic processes around synapses is also
variable. A close apposition of astrocytic processes should facilitate
binding and transport of synaptically released glutamate into
astrocytes (Barbour et al., 1994; Rothstein et al., 1994; Chaudhry et
al., 1995; Gundersen et al., 1995; Takahashi et al., 1997). In
cerebellar cortex, 3D reconstructions show that glial processes often
form a collar around the perimeter of the axon-spine interface (Palay
and Chan-Palay, 1974; Spacek, 1985). Single EM sections from
hippocampus show synapses with or without astrocytic processes (Lehre
and Danbolt, 1998; Rusakov and Kullmann, 1998a,b). Our
quantitative 3D analyses reveal that most of the large perforated synapses have astrocytes at their perimeters, although only
approximately one-third of the perimeter of individual perforated
synapses is surrounded. In contrast, fewer small macular synapses have
astrocytes at their perimeter, but those that do are more completely surrounded.
This nonuniform distribution of astrocytic processes raises the
question of whether they are randomly distributed or grow toward
specific synapses. Astrocytes in cell culture extend processes toward
substances that are released at synapses, including glutamate (Hatten,
1985; Cornell-Bell et al., 1990; Matsutani and Yamamoto, 1997). Several
factors will determine whether sufficient glutamate or other
astrotrophic substances escape from the synaptic cleft, including the
amount released and then diluted in the axon-spine interface.
Glutamate must escape from the synaptic cleft to the perimeter of at
least some of the hippocampal synapses, because glutamate transporter
currents occur in astrocytes when the synapses are activated (Bergles
and Jahr, 1997). The probability of glutamate being released during
synaptic transmission varies greatly among hippocampal synapses
(Hessler et al., 1993; Murphy and Segal, 1997; Liu et al., 1999; Ma et
al., 1999). Large perforated synapses have many docked vesicles and
thus might have a high probability of release (Harris and Sultan,
1995), which could explain why almost 80% of them have some astrocytic
processes at their perimeters. However, the large axon-spine interface
might substantially dilute the glutamate, which might explain why only
one-third of their perimeter is surrounded by astrocytic processes. The
smaller macular synapses have fewer docked presynaptic vesicles and
thus might have a lower probability of releasing glutamate (Harris and
Sultan, 1995), which might explain why almost one-half of the smaller macular synapses do not have astrocytic processes at their perimeters. However, when glutamate is released from a small synapse, the small
axon-spine interface will produce less dilution. Thus, glutamate released from a small synapse might escape from many parts of the
perimeter (i.e., 47% on average). These observations are consistent with the hypothesis that astrocytic processes preferentially surround synapses that have more glutamate escaping from their perimeters.
Whether a particular synapse will sense the glutamate that escapes from
the perimeter of its neighbor depends on uptake and dilution in the
extracellular space between them. Because most of the neighboring
synapses occur on different presynaptic boutons, glutamate diffusing
between them will reduce input specificity. The specific effect will
depend on the precise location of the glutamate receptors at the edge
or center of the PSD because of their different affinities for
glutamate (Lujan et al., 1997) How well EM images represent the volume
of ECS is controversial. Others have estimated that ECS should occupy
~20% of living brain volume (Nicholson and Sykova, 1998). Some of
the ECS might be lost during processing of fixed tissue because the
remaining ECS volume appears to be <20%, and there is a net 5-15%
overall shrinkage in fixed brain (Hillman and Deutsch, 1978; Cragg,
1980; Schuz and Palm, 1989). Others suggest that there is no net
shrinkage or loss of ECS in the EM images, and thus the distances
between synapses measured on EM sections might be reasonable estimates of the in vivo distances (Lehre and Danbolt, 1998). When the
tortuous path through the ECS was measured in 3D, the mean
center-to-center distance was 0.65 µm in stratum radiatum of area
CA1. In Rusakov and Kullmann (1998a,b), a linear distance of 0.436 µm
was calculated from stereological estimates of synapse density in
stratum oriens, and when multiplied by their tortuosity factor of 1.34, this value becomes 0.584 µm. Results from the modeling that account
for this uniform tortuosity and average linear distance between
synapses suggest that the effect of glutamate, even at high-affinity
glutamate receptors, will be reduced to ~17% (Rusakov and Kullmann,
1998a,b). No results have been presented for the larger distances
between synapses, although it can be assumed that the effect of
glutamate would be further diluted. Given the larger nearest
neighboring distances between synapses in stratum radiatum, it is
likely that only those receptors located at the edge of some of the
PSDs will be exposed to appreciable amounts of glutamate that might
have diffused from a neighboring synapse.
Physiological evidence for glutamate spillover between neighboring
synapses is controversial. Early evidence for substantial glutamate
spillover between hippocampal synapses was obtained in slices
maintained at room temperature (~25°C); however, much less occurs
at physiological temperatures (~37°C) because of an increase in the
activity or efficiency of glutamate transporters (Asztely et al.,
1997). The surface density of glutamate transporters on hippocampal
astrocytic membranes is high (~10,800
µm2) (Lehre
and Danbolt, 1998), but the rate of transport is slow (on the order of
milliseconds). Thus, the main effect of astrocytic glutamate
transporters on the submillisecond time scale will be to bind
glutamate, thereby buffering it from the extracellular space (Diamond
and Jahr, 1997; Rusakov and Kullmann, 1998a,b). If the astrocytes were
the only source of glutamate binding and uptake, one would not expect
temperature to have a profound effect on spillover because two-thirds
of the neighboring CA1 synapses have no astrocytic processes between them.
One possible explanation is that neuronal glutamate transporters also
remove glutamate from the axon-spine interface and ECS between
neighboring synapses. Whole-cell recordings from CA1 pyramidal cells
have not detected neuronal glutamate transporter currents (Bergles and
Jahr, 1998). However, if the neuronal glutamate transporters are
located at the synapse (Gundersen et al., 1993; Rothstein et al., 1994;
Lehre and Danbolt, 1998), then whole-cell recordings made at the soma
would not detect them. GLT1 was previously thought to be strictly an
astrocytic glutamate transporter; however, a variant of the GLT1
transporter may also occur on neurons (Torp et al., 1994, 1997; Berger
and Hediger, 1998; Chen et al., 1998; Eliasof et al., 1998). Recordings
from CA1 pyramidal cells show that glutamate is cleared less quickly
during synaptic activation from within the synaptic cleft in the GLT1
(/) knockout mice (Tanaka et al., 1997) than in wild-type mice,
which may be attributable to the absence of neuronal GLT1 at the
axon-spine interface. Neuronal GLT1 might also regulate glutamate
along the fine distal axonal and dendritic processes that separate
neighboring synapses.
Another possibility is that only the synapses that are releasing
substantial amounts of glutamate have astrocytic processes at their
perimeters (Fig. 8a).
Whole-cell recordings from hippocampal astrocytes show that astrocytic
glutamate transporter currents increase in parallel with transiently
elevated presynaptic release of neurotransmitter but do not remain
elevated during LTP (Diamond et al., 1998; Luscher et al., 1998). Thus,
the astrocytic processes are sampling synapses that are reliably
releasing glutamate but do not have increased release during LTP. Other
research suggests that LTP is partly or fully saturated at ~52% of
hippocampal synapses, so that subsequent experimental manipulations
produce little or no more LTP (Petersen et al., 1998). These synapses
might account for the ~58% of hippocampal synapses that have
astrocytic processes located at their perimeters. What about the
synapses that have no astrocytic processes at their perimeters? They
might undergo a change in the reliability or amount of glutamate
released during synaptic plasticity (Stevens and Wang, 1994; Liu et
al., 1999; Ma et al., 1999). As discussed above, astrocytic processes
could grow toward a synapse once glutamate levels get high enough for escape to occur from its perimeter (Fig. 8b). If such an
astrocytic response occurs quickly, or at low concentrations of
extracellular glutamate, then the newly formed astrocytic processes
might interrupt spillover and improve input specificity at newly
functional synapses.
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Figure 8.
Hypothetical model depicting how the differential
distribution of astrocytic processes at hippocampal synapses might
reflect synaptic activity. a, A previously releasing
synapse (Synapse 1) has an astrocytic process bordering
its perimeter where glutamate might otherwise escape from the
axon-spine interface. A synapse not releasing glutamate
(Synapse 2, dark gray) has no astrocytes
bordering its cleft. b, The astrocytic process has grown
toward Synapse 2 (no longer shaded) as changes in
synaptic function have caused it to release sufficient glutamate so
that some escapes from its perimeter.
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FOOTNOTES |
Received Dec. 17, 1998; revised May 26, 1999; accepted May 27, 1999.
This work was supported by National Institutes of Health Grants NS21184
and MH/DA57351, with the latter funded jointly by the National
Institute of Mental Health, National Institute on Drug Abuse, and
National Aeronautics and Space Administration (K.M.H.), and the Mental
Retardation Research Center Grant P30-HD18655 (Dr. Joseph Volpe,
PI). We thank Dr. John Fiala for creation of the
IGLtrace reconstruction system. We thank Dr. Craig Jahr,
Dr. Paul Rosenberg, and Dr. John Fiala for helpful discussions about this work.
Correspondence should be addressed to Dr. Kristen M. Harris, Department
of Neurology, Children's Hospital, Enders 208, 300 Longwood Avenue,
Boston, MA 02115.
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G. Sharma and S. Vijayaraghavan
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TOP
ABSTRACT
INTRODUCTION
Compound via MeSH
