Developmental Brain Research, 45 (1989) 103-111 103 Elsevier

BRD 50852

Ontogeny of somatostatin in cerebral cortex of macaque monkey: an immunohistochemical study

Akiko Yamashita, Motoharu Hayashi, Keiko Shimizu and Kiyoshi Oshima Department of Physiology, Primate Research Institute, Kyoto University, lnuyama, Aichi (Japan)

(Accepted 23 August 1988)

Key words: Somatostatin; Cerebral cortex; Primate; Ontogeny; Immunohistochemistry

Distribution of somatostatin-immunoreactive cells in the cerebral cortex of macaque monkeys at embryonic day 120 (E120), El40, newborn, postnatal day 60 (P60) and adult stages were studied by the avidin-biotin-peroxidase immunohistochemical method. At all stages, there existed 3 types of cells in the gray matter: bipolar, multipolar and small-sized cells which stained only in perikaryon. So- matostatin-immunoreactive ceils were observed from E120. The cell number increased between El20 and E140 and decreased until P60. At the newborn stage, a high density of cells was distributed in layer II of the prefrontal and parietal cortices (areas FD and PE). In layer I of the postcentral, parietal, temporal and preoccipital cortices (areas FA, PC, PE, TA, TE and OA), small numbers of hori- zontal cells were detected only at the embryonic and newborn stages. In adulthood, the number of somatostatin cells was much smaller than at the early stages (El40 and newborn). Compared to other cortical areas, in occipital cortex (area OC), there was little change in cell number during development. In occipito-temporal cortices, there were increases in cell number from posterior to anterior portion at all the stages. The large number of somatostatin cells in all layers of the cerebral cortex during the early stages indicates that somato-, statin plays a role in the development of the monkey cerebral cortex.

INTRODUCTION reported 9'12'41. Loss of memory function has also

been described in rats treated with cysteamine, Somatostatin is known as somatotropin-releasing which depletes cortical somatostatin 1,19. Our pre-

inhibiting factor in the mammalian hypothalamic tis- vious radioimmunoassay study 21 clarified that the

sue. In addition, biochemical and histochemical stud- concentration of somatostatin was high in the asso-

ies have revealed that the peptide is also present in ciated subdivisions of the cerebral cortex of adult ma- the cerebral cortex 2-5,14.16,1s,21.24,25.42. There have caque monkey. These findings suggest that the pep-

been some reports concerning the functions of the tide may participate in the higher functions such as

peptide in the cerebral cortex. On the cortical neu- cognition and memory. Moreover, the concentration

rons, somatostatin showed both excitatory and inhib- of somatostatin in monkey cerebral cortex was higher itory effects 11.3°.37. The peptide enhances the excita- at full-term period than in adulthood, suggesting that

tory effect of acetylcholine 27. Recently, co-existence somatostatin may also act as a neurotrophic factor 21.

with glutamic acid decarboxylase (GAD) or y-amino- To date, there are no reports concerning the onto-

butyric acid ( G A B A ) has been reported in the rat genic development of the peptide in the monkey ce- and monkey cerebral cortex by immunohistochemi- rebral cortex using an immunohistochemical method. cal methods 23,43. These results indicate the peptide The present study was performed to clarify: (1) so-

plays a role as neurotransmitter or neuromodulator matostatin-immunoreactive cell types, (2) the change in the cerebral cortex. Furthermore, in the cerebral in cell numbers, and (3) the distributional pattern of cortex of Alzheimer 's disease patients, a marked re- cells in the various developing cerebral areas of ma- duction of somatostatin immunoreactivity has been caque monkey by the avidin-biot in-peroxidase indi-

Correspondence: M. Hayashi, Department of Physiology, Primate Research Institute, Kyoto University, Inuyama, Aichi 484, Japan.

0165-3806/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)

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rectimmunohistochemical method, pentobarbital (Nembutal, 35 mg/kg i.p.) and per- A preliminary study has been reported elsewhere 49. fused through the hearts with ice-cold 0.15 M NaCI

followed by ice-cold Zamboni's fluid (2% parafor- MATERIALS AND METHODS maldehyde and 0.2% picric acid in 0.1 M phosphate

buffer, pH 7.4). The brains were dissected, cut into Macaque monkeys (Macaca fuscata fuscata, M. blocks and immersed in 30% sucrose containing

rnulatta and M. fascicularis) used in this study are 0.02% sodium azide in phosphate-buffered saline presented in Table I. In one adult monkey, colchicine (PBS), pH 7.4 at 4 °C. Fifty ~m sections were cut (500 ~g/kg) was injected into the lateral ventricles 2 with a frozen sliding microtome (Yamato Koki, To- days before sacrifice. We chose 5 different stages: kyo). The free-floating sections were preincubated in embryonic day 120 + 3 (El20), embryonic day 140 + methanol containing 0.3% H20 2 for 20 rain and in

3 (El40), newborn (Nb), postnatal 60 days (P60) and PBS-C [0.2% normal goat serum, 0.1% carrageenan adult (Ad). The reason we chose these stages is that (Sigma), 0.2% Triton X-100 and 0.02% sodium azide in the macaque monkey, the 6 layered celllular ar- in PBS] for 1 h at room temperature. Then the sec-

rangement is complete at E120 (ref. 38) and the larg- tions were incubated in anti-somatostatin rabbit anti- est number of synapses is observed at about P60 (ref. serum diluted by PBS-C at a dilution of 1:2000 for 72 39). h at 4 °C. The immunoreactive sites were visualized

To determine the embryonic days of fetus mon- by the avidin-biotin-complex-peroxidase method keys, we applied the timed mating method and mea- using the Vectastain ABC kit (Vector Labs, Burling- sured the length of head axis and crown-rump length ame, CA). A solution of 0.3% H202, 20 #g/ml 3.3'- using an ultrasonic transmission method (Sonolayer- diaminobenzidine tetrahydrochloride (Nakarai

graph, Toshiba, Japan). The fetuses were obtained Chemicals) in Tris-HCl buffer, pH 7.6, was used as from anesthetized pregnant monkeys by Caesarean the substrate for the peroxidase. Then the sections operation. We termed the normal delivery monkeys were mounted on gelatin-coated glass slides, dehy- after l60-170gestat ionaldaysasnewborn(Nb), drated in ethanol, cleared in xylene and cover-

All animals were deeply anesthetized by sodium slipped. Some sections were stained by Kresylechtvi- olett (Nissl staining) or hematoxylin eosin.

In order to check the specificity of this immunohis- TABLE I tochemical method, we replaced the primary anti-so-

Summary of experimentalmonkeys used matostatin antiserum with normal rabbit serum or preincubated with synthetic somatostatin-14 (Pep-

Age Sex Species Head axes (cm) tide Institute, Osaka, Japan) at a concentration of 10

El20 M M.f. 3.9 x 5.0 nmol/ml. The immunoreactivities completely disap- E120 M M.f. 3.9 x 5.1 El40 F M.f. 4.3 × 6.O peared. By the radioimmunoassay method, we ob- El40 F M.f. 4.6 × 5.7 served that the immunoreactivities to somatostatin- El40 M M.f. 4.5 x 5.7 14 and somatostatin-28 of this antiserum were almost Nb F M.f. 4.6 x 6.2 Nb F M.m. 5.2 x 6.4 the same. The other biochemical specificities of this Nb M M.m. 5.1 x6.7 anti-somatostatin antiserum have been described Nb F M.f.f. 5.2 x 6.4 previously20. P60 M M.m. 5.3 x 6.9 P60 F M.f. 5.3 x 6.1 Ad F M.f.* RESULTS Ad F M.f. Ad F M.f. Ad M M.f.f. Developmental pattern of somatostatin-immunoreac- Ad M M.f.f. tire cells

El20, embryonic 120 days; Nb, newborn; P60, postnatal 60 In general, at El20, somatostatin-immunoreactive days; Ad, adult; M.f., Macaca fuscicularis (Crab-eating mort- cells (SIRC) were detected in all areas examined and key); M.rn., M. mulatta (Rhesus monkey); M.f.f., M. fuscata there existed larger numbers of cells in subcortical fuscata (Japanese monkey); F, female; M, male; M.f.* was a colchicine-treatedanimal, white matter than in gray matter. Until El40 and

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newborn stage, the cell number increased and after and subcortical white matter. At P60, the distribution the newborn stage, it dramatically declined until P60. l~atterns of SIRC were similar to these at adulthood. Between P60 and the adult stage, there were a few In pre- and post-central gyri (areas FA and PC) differences in the cell number• At early embryonic (Fig. 2a,b), the number of SIRC at El20 was small in periods, the cells were distributed in all layers• Dur- both gray matter and subcortical white matter. The ing development, the number of cells became smaller, cell number increased until El40 and decreased especially in layer IV and subcortical white matter• gradually to adulthood. At adulthood, cells distributed in layer II, upper lay- In superior temporal lobe (area TA) (Fig. 3a), a er III, layer V, VI with a small number in white mat- small number of SIRC was found at El20. Until the ter. There was no difference in cell numbers between newborn stage, the cell number increased, and be- colchicine-treated and normal monkeys, tween newborn and P60, it declined especially in lay-

The developmental patterns of SIRC differed er IV and white matter. At P60, the cell number was among the various cortical areas, almost the same as at adulthood. There was a larger

In prefrontal and parietal association cortices number of SIRC in the anterior temporal lobe (area (areas FD and PE) (Fig. la,b), there were a small TG) than in the posterior temporal lobe (area TE) number of SIRC in gray matter and a relative large through all the stages examined (Fig. 3b). number in subcortical white matter at El20. Until In preoccipital cortex (area OA) (Fig. 4a), the El40, the number of SIRC increased and was distrib- number of SIRC increased until the newborn stage uted in layers I I -VI and in white matter. At the new- and after that it dramatically decreased until P60. In born stage, a high density of SIRC was observed in contrast, a relatively large number of the cells was layer II and cell numbers decreased in other layers found in occipital cortex (area OC) (Fig. 4b) at El20.

The cell number did not change through the develop- mental stages examined.

FD a

FA a E120 E140 Nb P60 Ad L~.. ( ~//~ ~.~

• " ":"" :';" ":" E120 E140 Nb P60 Ad

w m - - . " I ' , "

• i s wm I , : . . - - - ~ ~ • . • ' .

"" " ' " " ' ~ "" "' "J~ .. " ~ .." • • . . . •

PE

PC E120 E140 Nb P60 Ad

~ ~ i ~ w ~ t ~ ~ E120 ~ E140 N~ ~ i, i:ii ! - - Ad } wm w .:.. i *, .".: '

- - ' :" ; . . '~i . ' • -. wm -- ~. wm -- -- . wm wm .'~...

Fig. 1. Developmental changes of the distribution pattern of so- matostatin immunoreactive cells (SIRC) in prefrontal cortex (area FD) (a) and parietal cortex (area PE) (b). The dots rep- Fig. 2. Developmental changes of the distribution pattern of resent the immunoreactive cells• The side lines indicate the SIRC in motor cortex (area F A ) ( a ) a n d somatosensory cortex border between gray matter and white matter (wm). (area PC) (b).

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':, ~ 0 A a T A a / .

E120 E140 Nb P60 Ad E120 E140 N) P6( Ad

w . : - "1 i ~ :

w~ a ~',' ¢ "

• , ' , ' , b @ Nb b E120 E140 Nb P60 Ad

TG TE

.~..~ • .-::~ , , 0•

• o

• ~" . . wrr

• . %

Fig. 3. Developmental changes of the distribution pattern of SIRC in superior temporal cortex (area TA) (a). The distribu- Fig. 4. Developmental changes of the distribution pattern of tion pattern of SIRC at newborn stage in anterior portion (area SIRC in preoccipital cortex (area OA) (a) and occipital cortex TG) and posterior portion (area TE) of temporal cortex (b). (area OC) (b).

Somatostatin-immunoreactive cell types zontally over a long distance (Fig. 5c). At adulthood, We classified SIRC into 5 different cell types: this type of cells was not detected•

multipolar cells, bipolar cells, small-sized cells, layer The white matter cell was heavily stained and the I cells and white matter cells (Fig. 5). size was about 20-30~m in diameter (Figs• 5d and 7).

Multipolar cells were found in layer II-VI. Each This cell had long processes which spread in various had well-branched processes spread to various direc- directions with many varicosities. The longest pro- tions (Fig. 5a). In the lower layers (layers V and VI), cesses of this type of cells mainly went upward to- we observed this type of cell which spread vertical ward pia mater. Occasionally, the length was over processes long distances of over 100ffm (Fig. 6). The several hundred/zm long and reached gray matter bipolar cells had poorly branched processes and sent (Fig. 7). Larger numbers of this type of cells were these mainly in the vertical direction (Figs• 5b and 6). found during the embryonic periods• These two types of cells had many varicosities along the processes. The diameter of these cells was about DISCUSSION 20/~m. The small-sized cells stained only in the peri- karyon and the diameter was about 10 pm. Larger Developmental changes in somatostatin cell numbers numbers of this type of cells were distributed in the The increase in the number of somatostatin cells upper layers (layers II and III) than in the lower lay- during embryonic period followed by a decrease until ers (layers V and VI) (Figs. 5a and 6). adulthood agreed with our previous results using the

We observed layer I cells in somatosensory, pari- radioimmunoassay method 21. Recently the somato- etal, temporal and preoccipital cortices. This kind of statin cell number and the amount of preprosomatos- cell was found only during the embryonic and new- tatin mRNA were reported to decrease during devel- born stages. The cells spread their processes hori- opment in the rat cerebral cortex 8'33. This indicates

107

~,- . ÷

¢ r ¢ t L ." . . . . .

- " " .2;

Fig. 5. Various somatostatin immunoreactive cell types. Multipolar cells in layer II of area OB at E l 4 0 (arrows in (a)). Bipolar cell in layer VI of area PA at E l 2 0 (b). Small-sized cells which were stained only in the perikaryon (arrow heads in (a)). Cells in layer I of area PG at Nb which spread fibers vertically (c). Cells in white matter in area O A at E l 2 0 which had fibers with many varicosities (d). Bar = 5 0 y m .

108

a \

Fig. 7. Camera lucida drawings of SIRC in white matter at El20. Bar = 100pro.

does not change during development, the number of somatostatin cells co-existing with GABA is smaller at the embryonic than at adult stage. This indicates that the number of neurons which contain only so-

b matostatin is larger during the embryonic stage than at adult stage. Natural cell death is known to occur in the normal development of central nervous system 35. Reduction in the number of neurons has been re- ported in the monkey cerebral cortex during ontoge-

_ ny 34. Therefore the decrease of somatostatin cell number in the present study may be due to death of

~ ~ thosece l l swhichdonotco-ex is twi thGAng. If almost all somatostatin cells co-exist with

GABA during development, the number of somato- statin-GABA cells in the cerebral cortex is larger at embryonic stage than at adult stage. As the number

; ~ of GABAergic neurons seems not to decrease during Fig. 6. Camera lucida drawings of various SIRC at El20 in l ay- ontogeny, the somatostatin phenotype in the cortical erlI(a) and layer VI (b). Bar= 100~um. neurons may disappear in the course of develop-

ment. The transient presence of neuronal markers

that the level of mRNA regulates the amount of pre- has been described in both endocrine pancreas 46 and prosomatostatin in the cerebral cortex. Further study gut 45. Further immunohistochemical studies are nec- is required to determine the contents of the somato- essary to determine the number of GABAergic neu- statin mRNA in the monkey cerebral cortex, tons and the ratio of co-existence of somatostatin and

In adult macaque monkey, almost all somatostatin GABA during ontogeny.

containing cells are also GAD- or GABA-posi- tive 23'43. Our preliminary biochemical study revealed Developmental patterns of somatostatin cells among

that GAD activity in the monkey cerebral cortex only the various areas increased and did not decrease during develop- In association cortices such as areas FD, PE, TE ment 22. Furthermore, reduction in the number of and TA, the number of somatostatin cells was much GABA and GAD neurons has not been reported in higher during embryonic period than at adult period. developing cerebral cortex of mouse 15 or rat 28. We Particularly in areas FD and PE, high density of so- have two possible hypotheses concerning the reduc- matostatin cells was observed in layer II at the new- tion of somatostatin cells, born stage. In the primate, the association areas and

If the percentage of GABAergic neurons co- the layer II where the association fibers terminate existing with somatostatin to all GABAergic neurons are known to be well-developed 7. Furthermore, in

109

the occipito-temporal cortices, at all stages, there non-pyramidal cells: multipolar, bipolar and small-

were increases in the number of somatostatin cells sized cells. These three types of cells have been de- from OA to TE and TE to TG, following the visual scribed in various mammalian cortices 5A4,24,29,44.

information processing of the macaque monkeys 3z' Moreover we observed these types of cells at all 36,48. In temporal cortex of Alzheimer disease pa- stages examined. The somatostatin cells had varico- tients, somatostatinimmunoreactivity has been dem- sities along the well-branched processes even at onstrated in the neuritic plaque 3x and neurite tan- El20. Particularly in the deep layers (V and VI), so-

gle 4°. This indicates somatostatin neurons degener- matostatin cells had long processes reaching other ate in this type of dementia. In cysteamine-treated layers. These results indicate that even at the em-

rats, reduction in the performance of passive-avoid- bryonic period, somatostatin has effects on the local ance learning tasks has been reported 1,19. All these circuit in cerebral cortex.

findings suggest that somatostatin participates in the In layer I, somatostatin cells which spread fibers higher functions such as cognition and memory, horizontally over a few hundred/~m were observed

In preoccipital cortex, the number of somatostatin only during embryonic and newborn stages. This cells was larger at early stages than at adulthood. In type of somatostatin cell has been reported in the this area of macaque monkey, widespread interhemi- adult cat cerebral cortex 14. However, we did not find spheric fiber connections have been demonstrated this cell in the adult monkey, in agreement with other during early development ~3. In the rat occipital cor- studies 24'25. In white matter, we also found heavily

tex, both larger number of somatostatin cells 8 and the stained somatostatin cells which decreased in num- interhemispheric connections 26 have been reported ber during ontogeny. This cell spread branched pro-

during early periods. In contrast, in occipital cortex cesses over a long distance to reach the cortical layer. of macaque monkey, compared to other areas, we Recently, the same kind of MAP2 positive somato- observed no change in somatostatin cell number dur- statin cells has been described in white matter and ing development. Furthermore, the interhemispheric subplate of the developing cat telencephalon 1°. In de- connections of striate cortex of macaque monkey veloping kitten cortex, Valverde et al. 47 reported de- have not been reported even at early stages 13. In the crease of the number of subcortical ceils which have present study, we found many somatostatin cells dur- synapse contacting profiles. Some of these degener- ing embryonic stage in white matter and layer I, ating neuron-like cells in white matter may be the so- where many fibers of afferent and associated inputs matostatin cells which we observed in the present exist 7. Moreover, somatostatin has been reported to study. enhance the neurite outgrowth in molluscan neu- rons 6'17. These results suggest that somatostatin plays

a role in the formation of fiber network. ACKNOWLEDGEMENT

Developmental changes of somatostatin cells in the This work was supported by a grant from the Min-

cortical layers istry of Education, Science and Culture of Japan. In cortical gray matter, we observed 3 types of

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