1 Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, Umezono, Tsukuba, 305-8568, Japan, 2 Department of Cellular and Molecular Biology, Primate Research Institute, Kyoto University, Kanrin, Inuyama, Aichi 484-8506, Japan, 3 Division of Applied System Neuroscience, Advanced Medical Science Course, Nihon University School of Medicine, Oyaguchi-Kamimachi, Itabashi, Tokyo 173-8610, Japan
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Abstract |
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Key Words: GAP-43, plasticity, primate, protein kinase C, RC3
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Introduction |
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In the present study, we focused on the gene expression of neurogranin (also known as RC3, canarigranin, BICKS and p17; for a review, see Gerendasy and Sutcliffe, 1997), another major neuron-specific PKC substrate, which has been localized to postsynaptic dendrites (Represa et al., 1990
; Watson et al., 1992
). Among the PKC substrates, GAP-43 and neurogranin are the most closely related molecules having identical PKC phosphorylation sites and calmodulin-binding domains (Watson et al., 1990
; Baudier et al., 1991
; for reviews, see Gerendasy and Sutcliffe, 1997
; Chakravarthy et al., 1999
). Both GAP-43 and neurogranin bind calmodulin when they are not phosphorylated by PKC and release calmodulin as calcium-calmodulin in response to Ca2+ influx. Thus, GAP-43 and neurogranin are presynaptic and postsynaptic counterparts of calmodulin storage proteins. Like GAP-43, neurogranin and its mRNA are expressed at high levels in the developing rat brain. While the expressions decrease in most regions of the mature rat brain, high levels of expression remain in specific regions such as the hippocampus and cerebral neocortex (Represa et al., 1990
; Watson et al., 1990
). Although the precise role of neurogranin in the mature nervous system is not yet clear, there are several lines of evidence that relate the expression level with plasticity and memory function in the adult nervous system. Phosphorylation of neurogranin is enhanced during long-term potentiation and depression (Klann et al., 1993
; Pasinelli et al., 1995
; Ramakers et al., 1995
, 2000a,b; Chen et al., 1997
) and reduced expression has been observed in Alzheimers disease (Chang et al., 1997
; Davidsson and Blennow, 1998
). Further, neurogranin knockout mice have been shown to have impaired spatial learning (Pak et al., 2000
). Thus, the region-specific neurogranin expression in the adult central nervous system might reflect functional specialization which relates to postsynaptic plasticity in each region. In the present study, we performed a non-radioactive in situ hybridization histochemical analysis of the cerebral cortex of the macaque monkey to determine the localization and type of cells expressing neurogranin mRNA. We then quantified the expression levels of neurogranin mRNA in each area of the cerebral neocortex and each subregion of the hippocampal formation. Taken together with our previous studies investigating the expression of GAP-43 mRNA (Higo et al., 1998
, 1999; Oishi et al., 1998
), we suggest that both pre- and postsynaptic PKC substrates (GAP-43 and neurogranin) are abundant in several specific connections of the monkey brain. The preliminary results of these studies have been reported elsewhere (Higo et al., 2002b
,c).
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Materials and Methods |
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Brain tissue was obtained from 11 macaque monkeys (six Macaca fuscata and five M. mulatta) aged 2 or more years. Monkeys were purchased from a local provider, or were bred in the Primate Research Institute, Kyoto University. All animal experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals established by the Institute of Laboratory Animal Resources and the Guide for the Care and Use of Laboratory Primates established by the Primate Research Institute, Kyoto University. To investigate the effect of visual deprivation on the expression of neurogranin mRNA, five monkeys received tetrodotoxin (TTX, 15 µg in 10 µl of normal saline; Sigma, St Louis, MO), injected intravitreously into the right eye every fifth day for a total of 5 (n = 2), 10 (n = 2), and 30 (n = 1) days before they were killed. The monkeys were anesthetized with ketamine hydrochloride (10 mg/kg, i.m.) and pentobarbital sodium (Nembutal, 20 mg/kg, i.v.), prior to TTX administration. The pupillary light reflex of these monocularly deprived monkeys remained suppressed throughout the deprivation period.
The animals were pretreated with i.m. injections of ketamine hydrochloride (10 mg/kg) and deeply anesthetized by intravenous administrations of pentobarbital sodium (Nembutal, 35 mg/kg). The animals were then perfused through the ascending aorta with 0.5 l of ice-cold saline containing 2 ml (2000 U) of heparin sodium, followed by 25 l of ice-cold fixative containing 2% paraformaldehyde (PFA) and 0.5% glutaraldehyde in 0.15 M phosphate buffer (pH 7.4) or 2% PFA, 0.5% glutaraldehyde and 0.2% picric acid in phosphate buffer. During perfusion, the heads were chilled on crushed ice. After perfusion, the brains were immediately removed and blocked in the coronal plane (5 mm thick). The blocks were postfixed in 4% PFA and 5% sucrose and immersed in 30% sucrose for cryoprotection. The brain blocks were mounted in O.C.T. compound (Miles Inc., Elkhart, IN), rapidly frozen in a dry ice-acetone bath and stored at 80°C until dissection.
In Situ Hybridization
Brain segments from seven areas of the neocortex and the hippocampal formation were sectioned coronally to a thickness of 16 µm on a cryostat. We identified individual neocortical areas, including the prefrontal area (FD), the temporal association area (TE), the parietal association area (PG), the primary motor area (FA), the primary auditory area (TC), the primay somatosensory area (PB), and the primary visual area (OC), using the cytoarchitectonic criteria of von Bonin and Bailey (1947).
The procedure for in situ hybridization was performed as described in our previous report (Higo et al., 2003). Briefly, the sections on the slides were fixed in 4% PFA, treated with 30 µg/ml proteinase K (Roche Diagnostics, Germany) and dehydrated through a graded series of ethanols. Sections were prehybridized in 50% formamide, 600 mM NaCl, 1x Denhardts solution, 0.25% SDS, 10 mM TrisHCl (pH 7.6), 1 mM EDTA and 200 µg/ml tRNA for 3 h at 50°C. Following prehybridization, sections were transferred to hybridization buffer containing an additional 10% dextran sulfate and 1 µg/ml digoxigenin-labeled RNA probe, which was made from human RC3/neurogranin cDNA (pHRC3, 1.3 kb; a gift from Dr J.B. Watson, University of Calfornia, Los Angeles, CA). Hybridization was performed for at least 16 h at 50°C. The hybridized sections were washed with SSC and then treated with RNase A (30 µg/ml; Roche Diagnostics). Sections were then incubated for 1 h in diluted (1:500) anti-digoxigenin-alkaline phosphatase conjugate (DIG Nucleic Acid Detection Kit; Roche Diagnostics). Finally, the sections were incubated in color-developing buffer containing NBT and BCIP for 5 h.
The specificity of the probes was confirmed by Northern blot analysis, in which a specific 1.3 kb RNA transcript was observed (Fig. 1A). Intense signals for neurogranin mRNA were observed in all neocortical areas examined and weak signals were seen in the hippocampus. No signal was detected in the cerebellum. The lack of expression in the cerebellum is consistent with our previous report using a histochemical technique (Higo et al., 2003). In addition, control sections were hybridized by the method described above, using the sense probe for each mRNA. These control sections showed no specific signals (Fig. 1C).
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We quantified the expression patterns in the neocortex and the hippocampus using the same method that we used for the quantification of GAP-43 and MARCKS mRNAs (Higo et al., 1999, 2002d). Briefly, optical density (OD) was measured in each layer of a 300-µm-wide column that sampled all layers of the neocortex or each hippocampal subregion. The OD of the background staining in each section was measured in the subjacent white matter. Six columns from each cortical area and each hippocampal subregion (three columns from each of two sections) were measured for each monkey. We calculated the normalized OD of each layer or each subregion from in situ hybridized sections (in situ ODsignal in situ ODbackground). We also calculated the normalized OD from Nissl-stained sections (Nissl ODsignal Nissl ODbackground), which represent the cell density in each region. To compensate for differences of cell density among layers or subregions, we determined the ratio as follows (Figs 4, 5E and 8):
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We also represented the relative expression levels of mRNAs among subregions of the hippocampal formation by dividing the OD in each pixel of the digitized images of in situ hybridized sections by that of the adjacent Nissl-stained sections (Fig. 7), as described previously (Higo et al., 1998, 2002a). The OD was measured in each pixel of the digitized in situ hybridized (in situ pODsignal) and Nissl-stained sections (Nissl pODsignal). The ODbackground was estimated as the average of the ODs from five randomly sampled local regions of the white matter.
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Results |
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The laminar expression patterns of neurogranin mRNA were similar among areas FD, TE, PG, FA, TC and PB (Fig. 2B,D,F,H,J,L). Prominent hybridization signals were observed in the cell body and proximal dendrites of pyramidal cells in layers III, V, and VI (Figs 2B,D,F,H,J,L and 3A). We also observed prominent signals in the horizontal cells (Fig. 3B) and fusiform cells in these layers (Fig. 3C). Cells with the most intense signals were frequently observed in layer III (Fig. 2B,D,F,H,J,L). While the neurons in layers V and VI contained weaker hybridization signals than those in layers III, the proportion of positive neurons in layers V and VI tended to be larger than that in layer III. Signals were weak in the small round cells in layers II and IV. The large pyramidal cells in layer V of area FA also contained the hybridization signals (arrows in Figs 2H and 3D), but the signals were weaker than in neighboring smaller pyramidal cells in layer V and pyramidal cells in layers III and VI. No signal was observed in layer I (Fig. 2B,D,F,H,J,L). Quantitative analysis indicated that the hybridization levels (the neurogranin OD/Nissl OD ratios) in these areas were higher in layers III, V and VI than in the remaining layers (Fig. 4AF). Although detailed quantitative analysis has not been performed, most of the other neocortical areas excluding area OC showed similar laminar expression patterns to those in areas FD, TE, PG, FA, TC and PB.
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To investigate the effect of visual input on the expression of neurogranin mRNA in area OC, we performed in situ hybridization histochemistry in monkeys that had been deprived of monocular visual input via intraocular injections of TTX. After monocular deprivation for 5, 10, or 30 days, we observed a periodic pattern of staining for cytochrome oxidase in layer IV of area OC (Fig. 6B), indicating reduced neuronal activity of the ocular dominance columns that received visual input from the TTX-injected eye. However, we did not detect such a periodic ocular dominance pattern of staining for neurogranin mRNA after monocular deprivation for each period (Fig. 6C). Unequal distribution of neurogranin mRNA in layer IV correlated with the cell density revealed by Nissl-stained section (Fig. 6A). The hybridization pattern for neurogranin mRNA was identical to those for normal monkeys. These results indicate that the expression of neurogranin mRNA in area OC is not affected after monocular deprivation for these periods.
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In the entorhinal cortex and perirhinal cortex (areas 35 and 36), the hybridization signals were weaker than in the neighboring neocortical areas (areas TE and TA; Fig. 7B,C). In the amygdala, intense hybridization signals for neurogranin mRNA were observed in specific nuclei, such as the basal and lateral nuclei (arrowheads and double arrowheads in Fig. 7B,C). Intense signals were also observed in the claustrum (Fig. 7B,C).
In the hippocampal formation, the most intense hybridization signals were observed in the subiculum (Fig. 7E,F; see Fig. 3F). In the parahippocampal cortex, the signals were weaker than in the neighboring neocortical area (TEO) and the prominent signals were restricted to the deeper layers. Intense signals were observed in the striatum such as the caudate nucleus, but not in the thalamus such as the LGN (Fig. 7E,F). Quantitative analysis in the principal layers of the hippocampus indicated that the neurogranin OD/Nissl OD ratio was highest in the subiculum, higher in the CA3 and CA1 subfields of Ammons horn and weak in the dentate gyrus and CA4 subfield of Ammons horn (Fig. 8).
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Discussion |
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At least two previous studies reported the expression of neurogranin and its mRNA in the mature rat brain (Represa et al., 1990; Watson et al., 1990
). In general, our results in the monkey brain are consistent with the results in the rat brain in that the prominent mRNA expression for neurogranin was observed in the cerebral neocortex, hippocampus and striatum, but not in the thalamus and the cerebellum (Represa et al., 1990
; Watson et al., 1990
).
In the rat neocortex, the most intense hybridization signals for neurogranin mRNA were observed in large neurons in layers III, V and VI (Watson et al., 1990). The previous results in the rat neocortex are similar to the present result in most cortical areas of the monkey brain (areas FD, TE, PG, FA, TC and PB). However, the expression of neurogranin mRNA in layer IV of the visual area (area OC), which was observed in the monkey neocortex, has not been reported in the rat neocortex (Watson et al., 1990
). The specific laminar distribution of neurogranin mRNA in the visual area may be a characteristic of animals that have highly developed vision, such as primates. In the human, the distribution of neurons expressing neurogranin mRNA has been studied in only a few neocortical areas (temporal and frontal cortex; Chang et al., 1997
). The previous results in these areas of the human neocortex showing prominent hybridization signals in the pyramidal cells throughout layers IIVI are similar to our result in the monkey neocortex. A further experiment in the visual cortex is necessary to determine whether the specific laminar distribution of neurogranin mRNA is also present in the human primary visual area (area OC).
In the rat hippocampal formation, prominent signals were observed in the pyramidal cell layer of all regions. Among the hippocampal subregions, the CA3 subfield of Ammons horn has shown the most intense hybridization signals (Watson et al., 1990). Previous findings in the rat hippocampus differ from those of the present study in the monkey hippocampus, which showed the highest expression in the subiculum. Moreover, Northern and Western blot analyses in the rat have shown that the expression levels of both neurogranin mRNA and neurogranin protein were almost similar between the cerebral neocortex and hippocampus (Represa et al., 1990
; Watson et al., 1990
). The results in the rat are inconsistent with the present result from both the Northern blot analysis and in situ hybridization histochemistry in the monkey brain, which showed more intense hybridization signals in the cerebral neocortex than in the hippocampus. We previously reported that the expression patterns of GAP-43 and MARCKS, which are other PKC substrates, in the monkey hippocampus (Higo et al., 1998
, 2002d) were also different from those in the rat hippocampus (Kruger et al., 1992
; Yao et al., 1993
; McNamara and Lenox, 1997
). The phylogenetically different expression of these PKC-substrates may be related to the differential hippocampal function between these species.
Comparison with PKC and Type II Calcium/Calmodulin-dependent Protein Kinase
PKC consists of at least 11 isoforms. Previous histochemical studies of the monkey cerebral neocortex reported the region-specific distributions of several isoforms of PKC (Tominaga et al., 1993; Fukuda et al., 1994
). Among them, the expression of PKC
is similar to the expression of neurogranin. PKC
immunoreactivity is observed in the dendrites of pyramidal cells in layers II, III and VI of the primary motor area (area FA; Tominaga et al., 1993
). In the primary visual area (area OC), PKC
immunoreactivity is observed in layers II, IV and VI (Fukuda et al., 1994
). A previous knockout mouse study showed that stimulation of PKC with a phorbol ester increased neurogranin phosphorylation in wild type mice but failed to affect the phosphorylation in mice lacking PKC
(Ramakers et al., 1999
). Thus, phosphorylation of neurogranin in cortical neurons may be accomplished by PKC
.
Neurogranin is involved in the activity regulation of type II calcium/calmodulin-dependent protein kinase (CAMKII; Pak et al., 2000). CAMKII consists of four isoforms (
, ß,
,
) encoded by separate genes. Among them, the expression of CAMKII
in the monkey cerebral neocortex is similar to the expression of neurogranin mRNA. CAMKII
immunoreactivity is observed in the dendrites of pyramidal cells in layers IIVI of the monkey sensory-motor cortex (areas FA and PB; Jones et al., 1994
). In the primary visual area (area OC), CAMKII
immunoreactivity is observed in layer IV nonpyramidal cells as well as in pyramidal cells (Tighilet et al., 1998
). Thus, neurogranin may regulate CAMKII
activation in monkey cortical neurons. When monocular visual input is deprived for several (716) days by TTX injection, CAMKII
mRNA expression is increased in deprived ocular dominance columns (Tighilet et al., 1998
). This previous result is in contrast to our present result showing no deprivation effect on the expression of neurogranin mRNA. The expression level of CAMKII
mRNA and neurogranin mRNA may be regulated by different mechanisms.
The Expression of PKC Substrates in the Specific Connection of the Monkey Brain
In previous studies, we investigated the gene expression of GAP-43, another PKC substrate that accumulates only in presynaptic axon terminals (Nelson and Routtenberg, 1985; Meiri et al., 1986
, 1988; Skene et al., 1986
). From the subcellular distribution of neurogranin and GAP-43 proteins and our findings summarized in Table 1, we suggest that both postsynaptic PKC substrate (neurogranin) and presynaptic PKC substrate (GAP-43) are abundant in some specific connections (Fig. 9). (i) Intense hybridization signals for GAP-43 mRNA were observed in pyramidal cells in superficial layers as well as deep layers of the association areas (Higo et al., 1999
). The present result showed high levels of expression of neurogranin mRNA in layers III, V and VI of the neocortical areas. Thus, GAP-43 may be abundant in the presynaptic membrane and neurogranin may be abundant in the postsynaptic membrane of the corticocortical connections that originate from the association areas of the neocortex and terminate outside layer IV, which are the presumed feedback connections (Felleman and Van Essen, 1991
). (ii) We previously showed that intense hybridization signals for GAP-43 were observed in excitatory relay neurons in the LGN (Higo et al., 2000
), indicating that GAP-43 protein is localized in the geniculocortical axon terminals. Taken together with the present result in area OC showing intense hybridization signals for neurogranin mRNA in thalamic recipient neurons in layer IV, we concluded that both pre- and postsynaptic PKC substrates are abundant in the geniculocortical connections. (iii) In the hippocampus, intense signals for GAP-43 mRNA were observed in the pyramidal cell layer of Ammons horn (Higo et al., 1998
). In the present study, we observed intense hybridization signals for neurogranin mRNA in the subicular pyramidal cells. These results indicate that both PKC substrates are abundant in the connections between Ammons horn and the subiculum.
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Notes |
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Address correspondence to N. Higo, Systems Neuroscience Group, Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, Umezono, Tsukuba, Ibaraki 305-8568, Japan. Email: n.higo{at}aist.go.jp.
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