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Volume 16, Number 13, Issue of July 1, 1996 pp. 4135-4145
Copyright ©1996 Society for NeuroscienceUltrastructural Localization of the Vesicular Monoamine Transporter-2 in Midbrain Dopaminergic Neurons: Potential Sites for Somatodendritic Storage and Release of Dopamine
Melissa J. Nirenberg1, June Chan1, Yongjian Liu2, Robert H. Edwards2, and Virginia M. Pickel1 1 Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, and 2 Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, California 94143-0435
ABSTRACT
Midbrain dopaminergic neurons are known to release dopamine from somata and/or dendrites located in the substantia nigra (SN) and the ventral tegmental area (VTA). There is considerable controversy, however, about the subcellular sites for somatodendritic dopamine storage in these regions. In the present study, we used dual-labeling electron microscopic immunocytochemistry to localize the vesicular monoamine transporter-2 (VMAT2), a novel marker for sites of intracellular monoamine storage, within identified dopaminergic (tyrosine hydroxylase-containing) neurons in the rat SN and VTA. In dopaminergic perikarya, immunogold labeling for VMAT2 was localized to the Golgi apparatus, tubulovesicles that resembled smooth endoplasmic reticulum (SER), and the limiting membranes of multivesicular bodies. In dopaminergic dendrites, VMAT2 was extensively localized to tubulovesicles that resembled saccules of SER, and less frequently localized to isolated small synaptic vesicles (SSVs) or large dense-core vesicles (DCVs). In rare cases, VMAT2-immunoreactive SSVs were clustered within the cytoplasm of an SN or a VTA dendrite. Dopaminergic dendrites in the VTA contained a significantly higher number of immunogold particles for VMAT2 per unit area than those in the SN. Together, these observations support the proposal that dopamine is stored in and may be released from dendritic SSVs and DCVs, but suggest that the SER is the major site of dopamine storage within midbrain dopaminergic neurons. In addition, they provide new evidence that dopaminergic dendrites in the VTA may have greater potential for reserpine-sensitive storage and release of dopamine than those in the SN.
Key words: vesicular transport; ultrastructure; dendritic release; dopamine; monoamine; substantia nigra; ventral tegmental area; smooth endoplasmic reticulum; synaptic vesicle; dense-core vesicle; tubulovesicle; immunogold; neuroprotection
INTRODUCTION
Midbrain dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) play a critical role in the central regulation of motor and motivational functions (for review, see Roth and Elsworth, 1995). These functions are largely mediated by the release of dopamine from axon terminals in the striatum and cortex, but are also modulated through local somatodendritic release of dopamine in the SN and VTA (Björklund and Lindvall, 1975
Despite the evidence for vesicle-mediated exocytosis from midbrain dopaminergic neurons in the SN and VTA, ultrastructural studies have called into question whether there is a sufficient number of vesicles to account for the observed somatodendritic dopamine release. Dopaminergic dendrites in the SN contain clusters of electron-lucent vesicles and form dendrodendritic synapses, but these occur infrequently and are almost exclusively observed in the SN pars compacta (SNC) (Wilson et al., 1977
In the present study, we have used electron microscopic immunocytochemistry with a high titer antiserum directed against the vesicular monoamine transporter-2 (VMAT2), the vesicular monoamine carrier that is expressed in neurons (Erickson et al., 1992
MATERIALS AND METHODS
Antisera. An affinity-purified rabbit polyclonal antiserum directed against a synthetic peptide [(C)SYPIGDDEESESD] at the C terminus of VMAT2 was raised in rabbits as described previously (Peter et al., 1995Tissue preparation. The methods for tissue preparation and immunolabeling were based on those of Leranth and Pickel (1989)
Immunocytochemistry. All incubations were carried out at room temperature with agitation and were followed by several washes with PB, Tris-saline (TS) (0.9% NaCl in 0.1 M Tris, pH 7.6), or 0.01 M PBS. The sections were incubated overnight at room temperature in either (1) the VMAT2 primary antibody solution [anti-VMAT2 diluted 1:6000-1:15,000 in 0.1% bovine serum albumin-TS (for single labeling)]; (2) anti-TH diluted 1:10,000 in the VMAT2 primary antibody solution (for double labeling); or (3) the anti-VMAT2 primary antibody preadsorbed with an excess of the peptide sequence against which it was raised (as a negative control).
Sections that were prepared for double labeling used the avidin-biotin complex method (Hsu et al., 1981
diaminobenzidine (DAB) and 10 µl of 30% hydrogen peroxide in 100 ml 0.1 M TS, pH 7.6. They were then processed for immunogold-silver labeling, as described below.
All sections were labeled for VMAT2 using the silver-enhanced immunogold method (Chan et al., 1990
Electron microscopy. Sections that were prepared for electron microscopy were fixed in 2% osmium tetroxide for 60 min, dehydrated in a series of graded ethanols and propylene oxide, and flat-embedded in Epon 812 between two pieces of Aclar plastic. Ultrathin sections from the medial third of the SNC and SNR and from the parabrachial and paranigral portions of the VTA (Paxinos and Watson, 1986
5.2 mm and
Identification of labeled profiles. The classification of labeled profiles and subcellular organelles was based on the criteria of Peters et al. (1991)
Identification of subcellular organelles. Small synaptic vesicles (SSVs) were identified by their 30-60 nm cross-sectional diameter, round-to-pleomorphic shape, and electron-lucent lumen. Large dense-core vesicles (DCVs) were identified by their size (80-120 nm in cross-sectional diameter) and the presence of a characteristic electron-dense core surrounded by an electron-lucent halo. Tubulovesicles, many of which resembled saccules of SER (Broadwell and Cataldo, 1983
Data analysis. For quantitative analysis, the number of immunogold particles for VMAT2 per unit area (in µm2) was tabulated within a total of 1500 TH-immunoreactive dendritic profiles in three regions: the medial third of the SNC, the medial third of the SNR, and the parabrachial and paranigral subnuclei of the VTA. This tabulation was performed on a Dell 466/T computer (Austin, TX) using a Microcomputer Imaging Device system (Imaging Research, Ontario, Canada). To ensure consistency of the immunolabeling, and to eliminate potential concerns about differential tissue fixation or permeabilization, the same number of TH-immunoreactive dendritic profiles per region (50-150) was examined from each vibratome section. These profiles were sampled randomly from four vibratome sections, which were derived from two experimental animals. In each of the three regions, the number of gold particles per square micrometer of cross-sectional dendritic area was determined for 500 TH-immunoreactive dendritic profiles. The results are reported as the mean number of gold particles per unit area ± SEM, as calculated using a Fisher's Test for analysis of variance. Statistical significance was defined by a p value of <0.05.
RESULTS
Immunogold labeling for VMAT2 was localized to membrane-bound organelles in the cytoplasm of perikarya, dendrites, and axonal processes and terminals in both the SN and the VTA. As in previous studies (Nirenberg et al., 1995
Fig. 1. VMAT2 is localized to saccules of Golgi and multivesicular bodies in neuronal perikarya in the SN and VTA. A, Immunogold particles for VMAT2 are seen in the region of the Golgi apparatus (G) of a labeled perikaryon in the SNC, but are not detected in the adjacent rough endoplasmic reticulum (ER). The inset shows the boxed region at higher magnification. Immunogold labeling for VMAT2 is seen along the limiting membranes of two multivesicular bodies (mvb). B, Immunogold labeling for VMAT2 is localized to the Golgi apparatus (G) of a perikaryon in the VTA. Many of the gold particles contact lateral saccules of Golgi lamellae (curved arrows). The inset shows the boxed region at higher magnification. Gold particles are localized to saccules of Golgi (G) and associated vesicles and tubulovesicles (TV). Nu, Nucleus. Scale bars: A, B, 1 µm; inset in A, B, 0.2 µm.
[View Larger Version of this Image (212K GIF file)]
Fig. 2. In midbrain dendrites, prominent immunogold labeling for VMAT2 is localized to tubulovesicles that resemble smooth endoplasmic reticulum. A, B, A large dendrite in the SN (A) and two large dendrites in the VTA (B) contain immunogold labeling for VMAT2 that is primarily localized to large, electron-lucent tubulovesicles (TV) that resemble SER. Scale bars: A, 0.25 µm; B, 0.5 µm.
[View Larger Version of this Image (152K GIF file)]
Fig. 3. In SN dendrites, VMAT2 is localized to tubulovesicles of SER, and more rarely to SSVs or DCVs. A, In dually labeled tissue, gold particles for VMAT2 are seen within the cytoplasm of a medium-sized dendrite that also contains immunoperoxidase labeling for TH. The peroxidase reaction product is seen as an electron-dense precipitate throughout the cytoplasm, which is notably absent in dendrites processed only for VMAT2 (C). The immunogold particles are localized to tubulovesicles (TV) that are larger than the unlabeled synaptic vesicles (uV) seen in adjacent unlabeled axon terminals (UT). One of the unlabeled terminals (UT) forms a synaptic junction with the labeled dendrite (arrow). Scale bars: B, C, 0.5 µm. In larger dendrites, immunogold particles for VMAT2 are also localized to large tubulovesicles (TV), clusters of smaller SSVs, and an occasional DCV. Scale bars: 0.5 µm; inset, 0.2 µm.
[View Larger Version of this Image (204K GIF file)]
Fig. 4. In the VTA, VMAT2-labeled SSVs are sometimes clustered near dendrodendritic contacts. A, Immunogold labeling for VMAT2 and immunoperoxidase labeling for TH are seen in two large dendrites (De). Some of the immunogold particles are localized to a cluster of small synaptic vesicles (V) and larger electron-lucent tubulovesicles (TV) near a point of contact (straight arrow) between the two dendrites (De). A similar cluster of vesicles and tubulovesicles (curved arrow) contains no detectable immunogold labeling in the observed plane of section, but contained several immunogold particles for VMAT2 in a serial section (not shown). A VMAT2-labeled dense-core vesicle (DCV) is also seen in the ``presynaptic'' dendrite. B, In a section processed for single labeling, immunogold particles for VMAT2 are localized to a cluster of small synaptic vesicles (V) in a dendrite (De) near its site of contact (arrow) with an unlabeled dendrite (UDe). The labeled vesicles are similar in size to the unlabeled synaptic vesicles (uV) seen in an adjacent unlabeled terminal (UT). Scale bars: A, B, 0.5 µm.
[View Larger Version of this Image (208K GIF file)]
Fig. 5. In rare cases, VMAT2-labeled vesicles are localized to dendritic spines in the SNR and the VTA. A, B, Immunogold labeling for VMAT2 and immunoperoxidase labeling for TH are colocalized in two dendrites in the SNR. Immunogold particles are localized to small synaptic vesicles (V) in dendritic spines (Sp). These vesicles are similar in size to the unlabeled small synaptic vesicles (uV) seen in adjacent unlabeled axon terminals (UT). C, Gold particles for VMAT2 are localized to a tubulovesicular organelle (TV) in a dendritic spine in the VTA. The labeled tubulovesicle is larger than the synaptic vesicles seen in an adjacent unlabeled axon terminal (UT). De, Dendrite. Scale bars: A-C, 0.5 µm.
[View Larger Version of this Image (197K GIF file)]
Fig. 6. In the SN and VTA, VMAT2 is localized to SSVs and DCVs in axon terminals that usually lack detectable TH-immunoreactivity. A, Immunogold particles for VMAT2 are localized to small synaptic vesicles (V), an isolated DCV, and the plasma membrane (closed arrow) of an axon terminal in the SN that lacks detectable peroxidase reaction product for TH. The VMAT2-containing terminal forms a synaptic contact (open arrow) with a dendrite (De) that contains intense peroxidase reaction product for TH, but no detectable immunogold labeling for VMAT2. B, Immunogold particles for VMAT2 are seen in two axon terminals in the SN. The terminal at the top contacts a dendrite (De) that is labeled with immunoperoxidase for TH and immunogold for VMAT2. The terminal at the bottom contains numerous VMAT2-labeled large dense-core vesicles (DCV). The VMAT2-immunoreactive terminals contain no detectable peroxidase labeling for TH. UT, Unlabeled terminal. C, Immunogold particles for VMAT2 are localized to small synaptic vesicles (V) and a larger electron-lucent tubulovesicular structure (TV) in an axon terminal in the VTA that lacks detectable peroxidase reaction product for TH. The VMAT2-labeled terminal contacts a dendrite (De) that is lightly immunoperoxidase-labeled for TH. D, An axon terminal in the VTA contains immunogold particles that are localized to the membranes of large dense-core vesicles (DCV) and small synaptic vesicles (V). The VMAT2-labeled terminal contains no detectable peroxidase reaction product for TH. Scale bars: A-D, 0.5 µm.
[View Larger Version of this Image (184K GIF file)]
Perikarya
Neuronal perikarya in both the SN (Fig. 1A) and the VTA (Fig. 1B) contained extensive immunogold labeling for VMAT2. This immunogold labeling was localized most prominently to tubulovesicular organelles, most of which resembled saccules of SER (Peters et al., 1991Dendrites and dendritic spines
In the SN, VMAT2-containing dendritic profiles were distributed throughout the pars compacta and the pars reticulata. Within the VMAT2-labeled dendrites, most of the immunogold labeling was associated with large tubulovesicles that had the morphological appearance of dendritic SER (Peters et al., 1991In tissue that was dual-labeled for both VMAT2 and TH, most of the VMAT2-labeled dendrites also contained detectable peroxidase reaction product for TH (Fig. 3A). Although the VMAT2-labeled dendrites in the SN were sometimes apposed to and/or received synaptic contacts from unlabeled axon terminals (Fig. 3A) or dendrites (not shown), they were only rarely apposed to other VMAT2- or TH-labeled dendrites.
On several occasions, immunogold labeling for VMAT2 was detected in dendritic spines in the SNR (Fig. 5A,B). Within these spines, VMAT2 was associated prominently with electron-lucent vesicles and tubulovesicles (Fig. 5A,B). The labeled spines were frequently apposed to and/or received asymmetric contacts from unlabeled terminals. In some cases, these unlabeled axon terminals contacted both the spine and the shaft of the same VMAT2-containing dendrite. In sections that were double-labeled with immunogold for VMAT2 and immunoperoxidase for TH, most of the VMAT2-labeled spiny dendrites contained detectable reaction product for both markers (Fig. 5A,B).
In the VTA, as in the SN, immunogold labeling for VMAT2 was localized most prominently to tubulovesicles that resembled saccules of SER (Fig. 2B). Less frequently, immunogold labeling was localized to smaller electron-lucent vesicles that resembled SSVs (Fig. 4A,B) or to DCVs (Fig. 4A). In several cases, clusters of VMAT2-labeled vesicles were observed near segments of the dendritic plasma membrane that were apposed to and/or formed dendrodendritic synapses onto other dendrites. Some of the apposed dendrites contained (Fig. 4A) and some lacked (Fig. 4B) detectable VMAT2 immunoreactivity. In sections that were dual-labeled for both VMAT2 and TH, many of the of the pre- and/or postsynaptic dendrites in which there was immunogold labeling for VMAT2 also contained peroxidase reaction product for TH (Fig. 4A). VMAT2 also was detected occasionally in dendritic spines in the VTA (Fig. 5C). Within these spines, VMAT2 was selectively associated with vesicles and tubulovesicles (Fig. 5C).
By quantitative analysis, there were significantly more gold particles for VMAT2 per unit area within TH-immunoreactive dendrites in the VTA (1.78 ± 0.10/µm2) than in TH-immunoreactive dendritic profiles in either the SNC (1.30 ± 0.07/µm2; p < 0.0001) or the SNR (1.22 ± 0.07/µm2; p < 0.0001). In contrast, when TH-immunoreactive dendrites in the SNC and SNR were compared, there was no statistical difference in the density of immunogold labeling for VMAT2 (p = 0.47).
Axons and axon terminals
Immunogold labeling for VMAT2 was frequently detected in axon terminals and in small, unmyelinated axons in the SN (Fig. 6A,B) and VTA (Fig. 6C,D). Within the labeled axonal processes, gold particles for VMAT2 were localized predominantly to the membranes of SSVs (Fig. 6A,C,D) or DCVs (Fig. 6A,B,D) and only infrequently to larger tubulovesicles (Fig. 6C). In rare cases, one or more immunogold particles seemed to contact the cytoplasmic surface of the plasma membrane of an axon terminal that contained VMAT2-labeled vesicles (Fig. 6A).In sections that were dually labeled with immunogold for VMAT2 and immunoperoxidase for TH, a small number of unmyelinated axons in the SN and the VTA contained immunoreaction product for both markers. The majority of the VMAT2-containing unmyelinated axons in the SN (Fig. 6A,B) and the VTA (Fig. 6C,D), however, did not contain detectable immunoreaction product for TH. This was the case even when other TH-immunoreactive structures were clearly observed within adjacent profiles within the same tissue section (Fig. 6A-C). The VMAT2-labeled axon terminals in both regions were frequently apposed to, and in some cases formed synaptic junctions with, TH-labeled dendrites, as illustrated in the VTA (Fig. 6C) and SN (Fig. 6A).
DISCUSSION
This is the first study to examine the ultrastructural localization of VMAT2 within midbrain dopaminergic neurons. Our results show that within dopaminergic perikarya and dendrites in the SN and VTA, VMAT2 is extensively localized to tubulovesicles that resemble SER, and only rarely localized to SSVs and DCVs. These findings suggest that the SER is the major site of reserpine-sensitive somatodendritic dopamine storage in these regions. We have also shown quantitative differences in the levels of expression of VMAT2 in dopaminergic dendrites in the SN and VTA. These differences may contribute to the differential levels of somatodendritic dopamine release in the SN and VTA and/or to the differential susceptibility of the dopaminergic neurons in these regions to parkinsonism-inducing neurotoxins.Methodological considerations
The subcellular localization of VMAT2 to saccules of Golgi tubulovesicles of SER and vesicles in the SN and VTA is consistent with electron microscopic studies of uptake of false neurotransmitters and radiolabeled monoamines, which have identified these organelles as potential sites of monoamine storage (Cuello and Iversen, 1978Dopaminergic perikarya: potential sites of membrane synthesis and recycling
The pattern of VMAT2-immunolabeling along saccules of Golgi, tubulovesicular organelles, DCVs, and occasional MVBs in TH-immunoreactive (dopaminergic) perikarya in the SN and VTA was similar to the distribution of VMAT2-immunolabeling that we showed previously in the nuclei of the solitary tract (NTS) (Nirenberg et al., 1995Although the VMAT2-labeled perikaryal organelles may include sites of nonfunctional expression of VMAT2 or its C-terminal domain, experiments using the uptake of false neurotransmitters have shown evidence that the trans-Golgi apparatus, DCVs, and tubulovesicles that resemble SER in SN perikarya can sequester monoamines (Wilson et al., 1977
Dopaminergic dendrites: potential sites of dopamine storage and release
We have shown that small numbers of VMAT2-containing SSVs are present in the cytoplasm of dopaminergic dendrites and dendritic spines in both the SN and VTA. These findings are consistent with those of false neurotransmitter uptake studies, which have demonstrated that the dendrites of dopaminergic neurons in the SN contain relatively few synaptic vesicles with a functional monoamine uptake carrier (Sotelo, 1971Dopaminergic perikarya and dendrites in the SN and VTA were also filled with extensive networks of VMAT2-labeled tubulovesicles. In fact, some of the organelles that have met our morphological criteria for SSVs may have been tubulovesicular structures, which can be indistinguishable from SSVs when examined in cross-section (Ayala, 1994
Given the limited detection of VMAT2-containing vesicles, the VMAT2-containing tubulovesicular organelles are likely to represent the major site of reserpine-sensitive dopamine storage in the SN and VTA. Thus, these tubulovesicular organelles probably contribute more significantly than SSVs or DCVs to somatodendritic dopamine release (Mercer et al., 1979
Nondopaminergic terminals: potential sites of storage and release of other monoamines
In addition to the TH-immunoreactive perikarya and dendrites, we have also observed numerous VMAT2-immunoreactive axon terminals in both the SN and the VTA. These VMAT2-containing axonal processes almost never contained detectable TH-immunolabeling, but were frequently apposed to and/or formed synaptic contacts with dopaminergic (TH-immunoreactive) dendrites in both the SN and the VTA. The presence of VMAT2 immunolabeling and absence of detectable TH-immunolabeling in these axon terminals suggests that they contain monoamines other than catecholamines. In particular, serotonergic neurons in the raphe nuclei are known to make dense projections to both dopaminergic and nondopaminergic dendrites in the SN (Fibiger and Miller, 1977Differential localization of VMAT2 in the SN and VTA: functional implications
Dopaminergic neurons in the SN and VTA are known to differ markedly in their roles in motor and motivational functions, their biochemical and pharmacological properties, and their susceptibility to exogenous neurotoxins and neurodegenerative disease (for review, see Roth and Elsworth, 1995Recent evidence has also shown that vesicular monoamine transporters can confer neuroprotection by sequestering dopamine neurotoxins such as 1-methyl-4-phenylpyridinium (MPP+) that have been used in experimental models for Parkinson's disease (Liu et al., 1992a
FOOTNOTES
Received March 4, 1996; revised April 5, 1996; accepted April 11, 1996.
This research was supported by National Institute of Mental Health (NIMH) Grants MH00078 (V.M.P.) and MH40342 and by the National Institute on Drug Abuse (Grant DA04600). R.H.E. is supported by NIMH Grant MH50712 and by a National Alliance for Research on Schizophrenia and Depression Established Investigator Award. We thank Drs. Carrie T. Drake and Adena L. Svingos for helpful critical commentary, and Ms. Joy Hornung for photographic assistance.
Correspondence should be addressed to Dr. Melissa J. Nirenberg, Department of Neurology and Neuroscience, Cornell University Medical College, 411 East 69th Street, Room KB-410, New York, NY 10021.
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ABSTRACT
