ARTICLE |
Correspondence to: James C. McKenzie, Dept. of Anatomy, College of Medicine, Howard University, 520 W St, NW, Washington, DC 20059. Fax: 202-265-7055.
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Summary |
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Atrial natriuretic peptide (ANP) has previously been localized in areas of mammalian brain associated with olfaction, cardiovascular function, and fluid/electrolyte homeostasis. Despite the presence of several types of natriuretic peptide receptors in mammalian cerebellum, neither intrinsic nor extrinsic sources of the natriuretic peptides have been described. In this report we describe the immunohistochemical localization of both intrinsic and extrinsic sources for ANP in human cerebellum. ANP-like immunoreactivity (ANP-LIR) was observed in climbing fibers in the cerebellar molecular layer that probably originated from isolated immunopositive neurons of the inferior olivary complex. Intrinsic sources of ANP-LIR included small subpopulations of protoplasmic and fibrous astrocytes and Bergmann glia, as well as Golgi and Lugaro neurons of the granule cell layer. These results suggest that, in addition to its presumptive roles in local vasoregulation, ANP may serve as a modulator of the activity of Purkinje neurons. (J Histochem Cytochem 49:14531467, 2001)
Key Words: ANP, cerebellum, Golgi neurons, astrocytes, Bergmann glia, inferior olive, climbing fibers
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Introduction |
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NATRIURETIC PEPTIDES and their mRNAs have been localized to forebrain and brainstem regions associated with olfaction, blood pressure regulation, and fluid/electrolyte balance in several species (
In stark contrast to the above studies, data from human cerebellum demonstrate significant levels of both ANP and BNP (
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Materials and Methods |
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Five human subjects (see Table 1), received within 3 hr of death, were perfused via the carotid and vertebral arteries with 10% neutral buffered formalin (NBF) as previously described (
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Immunohistochemical staining was performed by the avidinbiotinperoxidase complex (ABC) technique (Vectastain Elite; Vector Laboratories, Burlingame, CA) using a previously well-characterized antibody against synthetic rat ANP IV (a gift from Dr. Tadashi Inagami) at dilutions of 1:10,00030,000. Rat ANP-IV with the amino acid sequence H2N-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-COOH (hANP428), and 28% with atriopeptin I, but did not crossreact with argininevasopressin, angiotensin I (AI), or angiotensin II (AII) (
Free-floating sections were pre-incubated in PBS, pH 7.4, containing 3% normal goat serum (NGS) and 0.3% Triton X-100 for 30 min at room temperature and then transferred to PBS containing 1.5% NGS, 0.3% Triton, and primary antibody (1:10,00030,000) for 72 hr at 4C. After washing (three times for 5 min in PBS/0.1% Triton), sections were incubated for 30 min in biotinylated goat anti-rabbit IgG (1:200) in PBS/0.3% Triton. The tissue was then washed as above and incubated for 30 min in PBS containing 1% H2O2, washed, and incubated for 30 min in ABC complex in PBS/0.3% Triton. Finally, the sections were incubated for 5 min in 0.05 M Tris buffer (pH 7.2) containing diaminobenzidine (35 mg%) and H2O2 (0.005%) and washed overnight in tapwater. Frozen sections were mounted on glass slides, dehydrated, cleared, and coverslipped. Substitution of normal rabbit serum for primary antibody served as a control. Sections were viewed and photographed in an Olympus Vanox microscope. The ANP IV antibody was further characterized by blot immunostaining. Serial concentrations (1.0 x 10-41.0 x 10-11 g) of peptide standards (rat ANP428, human ANP128, human ANP128 antiparallel dimer, BNP-32, rat BNP-45, human CNP: Peninsula Laboratories, Burlingame, CA) were applied to Immobilon PVDF transfer membrane (Milllipore; Bedford, MA) through a 96-well plate and incubated with ANP IV antibody (1:50,000) for 1 hr. Subsequent processing followed the directions given in the Vectastain elite kit (Vector Laboratories). Previous studies have demonstrated that the ANP antibody does not crossreact appreciably with BNP or CNP in absorption controls (
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Results |
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The results of the present study demonstrate conclusively the localization of ANP-like immunoreactivity (ANP-LIR) in specific subpopulations of both neurons and astrocytes in the human cerebellar cortex. Specimens from all cases yielded similar results. There were no obvious differences in the types and sizes of ANP-positive astrocytes found in various regions of the cerebellar hemispheres, flocullus, nodulus, or vermis. Intensity of staining was directly correlated with the concentration of antibody and staining was completely abolished by substitution of non-immune serum for primary antibody. Blot immunostaining revealed maximal reactivity of ANP IV antibody with rat ANP IV and significant reactivity with hANP128. There was no apparent reactivity of the antibody with either BNP or CNP (Fig 1).
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Protoplasmic Astrocytes
Immunoreactive astrocytes with many short, thick processes were distributed sparsely throughout the granular layer of the cerebellar cortices (Fig 2A). These astrocytes were similar in appearance to those of the cerebral gray matter (
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Fibrous Astrocytes
Immunoreactive astrocytes identical in morphology to those observed in human cerebrocortical white matter were scattered very sparsely throughout the cerebellar white matter (Fig 2B). These ANP-positive astrocytes were characterized by the length of their fine processes, which occasionally appeared to possess varicosities. The mean size of fibrous astrocytes, including stained processes, was 338.57 x 110.71 mm.
Bergmann Glia
The most numerous subpopulation of ANP-immunoreactive astrocytes in human cerebellum was identified as Bergmann glia, based on the position of their cell bodies near the granular layer/Purkinje cell interface and the extension of feather-like processes across the width of the molecular layer to the pial surface (Fig 6).
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Neurons
Sparsely distributed ANP-immunoreactive neurons were observed in all regions of the human cerebellar cortex. Although relatively few of each type were observed, ANP-immunoreactive neurons fell into two categories based on morphology and orientation within the granule cell layer. The most numerous, the typical cerebellar Golgi neurons, were frequently found in the granular layer near the Purkinje cell zone but were also observed more centrally disposed within the granule cell layer or occasionally near the white matter. The soma was generally polygonal, with four or more primary dendritic branches. Although the origin of the axon was not identifiable, many delicate, finely beaded collaterals were observed in the area surrounding the soma, extending for variable distances throughout the granule cell layer and occasionally penetrating adjacent folia (Fig 7). Often these immunoreactive collaterals occupied as much as one half of the cross-sectional area of a single folium. A presumably related neuron type was moderately to intensely immunoreactive, possessed an oval soma of medium size, and was always observed in the granular layer immediately subjacent to the Purkinje cell layer (Fig 8). The long axis of the soma and its major dendritic process was oriented parallel to the interface of the granular and Purkinje cell layers. Secondary dendritic processes and a profusion of varicose axon collaterals extended deeply into the granular layer, while a few axon collaterals branched among the Purkinje cells. These neurons are morphologically similar to those known as the cells of Lugaro (
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Immunoreactive climbing fibers were occasionally observed following the trajectory of Purkinje dendritic arborizations in the molecular layer (Fig 9). Immunoreactive fibers were not routinely identified in the cerebellar white matter, and climbing fibers could not be unequivocally identified in the granule cell layer. However, the presence of immunoreactive fine varicose fibers branching in concert with, and following a similar path to, the Purkinje cell dendritic arborization characterized these processes as climbing fibers. Relatively few (one or two) ANP-LIR climbing fibers were observed in each section. These fibers most likely originated in a population of ANP-IR neurons sparsely distributed in all components of the inferior olivary complex, including the medial and superior accessory nuclei (Fig 10). The numbers of immunoreactive inferior olivary neurons appeared to correspond closely to the number of ANP-positive climbing fibers. Fig 11 shows the distribution of ANP-positive neurons, fibrous and protoplasmic astrocytes, and Bergmann glia in a camera lucida drawing of a typical frozen section.
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Discussion |
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The demonstration of functional natriuretic peptide receptors behind the bloodbrain barrier in the mammalian cerebellum virtually demands sources of natriuretic peptides either within the cerebellum itself (intrinsic) or elsewhere within the central nervous system (extrinsic). The results of the present study demonstrate the cellular localization of ANP-LIR within the human cerebellum and strongly suggest that at least some cerebellar ANP is synthesized intrinsically, while one extrinsic source is located in the inferior olive.
ANP-LIR, as detected in the present study, represents localization of ANP and not one of the other natriuretic peptides (BNP, CNP) because results of blot immunostaining revealed no apparent crossreactivity of ANP IV antibody with either BNP or CNP, even at relatively high peptide concentrations. The antibody was raised against a purified synthetic ANP IV and its specificity and sensitivity have previously been well characterized in various tissues (
In contrast to our current results in human cerebellum, previous studies of ANP distribution in rat brain have failed to demonstrate ANP-positive cells (
In addition to ANP, other members of the natriuretic peptide family have been detected in the cerebella of various species. Low levels of BNP have been reported in porcine cerebellum (
The presence of intrinsic or extrinsic sources of ANP-like peptides in mammalian cerebellum was originally suggested by several studies reporting species-specific localization of ANP-binding sites. Binding sites for ANP have been reported to be absent (
A most interesting result of the present study was the localization of ANP-LIR in climbing fibers of the human cerebellum. This was strongly supported by detection of strong ANP-LIR in the perikarya and axonal processes of neurons in the inferior olive. It has long been established that the inferior olive is the sole source of cerebellar climbing fibers (
Localization of ANP in Golgi and related Lugaro neurons of the granule cell layer, in addition to climbing fibers, suggests that ANP may play a role as a neurotransmitter or neuromodulator in regulation of Purkinje cell function. A similar role has been proposed for ANP in the hypothalamus, where ANP alters the activity of vasopressinergic neurons (
ANP is unique in its localization to a subpopulation of inferior olivary complex neurons and climbing fibers that persists through adulthood in human brain. Aspartate, an excitatory amino acid, is presumed to be the primary neurotransmitter in climbing fibers (
In the present study, ANP-LIR was also localized in protoplasmic, fibrous, and Bergmann astrocytes of human cerebellum. Previously, we have demonstrated similar subpopulations of ANP-positive astrocytes in canine (
At this time, the functional significance of ANP in cerebellar astroglia remains speculative. We have previously suggested that ANP synthesized in astrocytes of the canine and human cerebral cortices (
The natriuretic peptides may play a role in the regulation of development and cell growth in the cerebellum. ANP has been shown to inhibit mitogenesis and cell growth in several systems, including mesangial cells (
We have demonstrated both neuronal and glial intrinsic sources of ANP-LIR in human cerebellum as well as an extrinsic source in climbing fibers originating from the inferior olivary complex. The various roles of cerebellar ANP derived from these sources, as well as regulatory mechanisms, remain to be elucidated by electrophysiological and molecular biological studies, but are likely to include both local vasoregulation and modulation of Purkinje cell output.
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Acknowledgments |
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Supported in part by a Howard University Faculty Research Support Grant (to JCM), AHA Heartland Affiliate (to RMK), and NIH grants HL 45241 (to JCM) and P30NS32399 (to NEJB and RMK).
Received for publication October 25, 2000; accepted May 23, 2001.
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