Thyroid hormone and development of the rat hippocampus: Morphological alterations in granule and pyramidal cells

THYROID HORMONE AND DEVELOPMENT OF THE RAT HIPPOCAMPUS: MORPHOLOGICAL ALTERATIONS IN GRANULE AND PYRAMIDAL CELLS* A.

RaM1.t

A. J. PATI:I_: and .4. RAISINt

Laboratorre de Phbslologic comparcc. tUA II97 du CNRS “Neuroblologie cndocrmologiquc”. LJnivcrsitC des Sciences et Techniques du Langusdoc. 33060 Montpelller Cedex. France: .Intl ZMRC Developmental Neurobiology (Jnit. Institute of Neurology. 73 John’s Me\+\. London WCIN 7NS. I’.K Abstract-A quantitative study of the morphogcnesi? of granule and pyramidal cells was pcrlormed on Golgl Cox preparations of the developing hippocampus of norm‘tl and h> path! roid rats. and hy pothh~-old rats given replacement thyroxine treatment. In the normal hippocampus. the volume of the ccl1 hod! .cnd the number of branching points on the apical and on the ba\al dendrites of pyramldai ccII\ increased between 6 and IO days after birth. The pyramidal cells of Ammon‘s horn showed a gradation from rirca CAI to area CA4 of progressive differentiation. In thyroid-deticlent rats. the arhoriration of the dendritlc field of both granule and pyramidal cells was impaired, and for pyramIda cells the cxtcnt of the impairment depended on the position of the cells In the Amman‘s horn. the cells of CA3 1 .ireas helng the most affected. Treatment of hypothyroid rats with a physiological dose of thyroxine rcstorcd ~mc of the morphological defects to normal, but others were altered beyond control levels. Indrcatlng that thyroid hormone differentially controls not only the measured indices of maturation hut :~Iw that II\ influence depends on the position of the pyramidal cells The observations were consistent with the concept that thyroid hormone is important 1n the establishment of the CA1 to CA4 gradient of pyramidal cell dlffcrrntiatlon and in the dc\clt~pmcnt 01 the spatiotemporal relationship between pyramidal and granule cells of the hippocampus

The hippocampus is a structure with only a feu major cell types and well-defined inputs and outputs, providing a unique opportunity to study cell formation. migration and differentiation in this brain region (for references see Refs I I and 33). Several Golgi studies on the development of the hippocampus have shown marked changes in the growth of neurons, the elaboration of their processes. and the overall interconnections,‘.” I’)L’.‘?.!X Development of the dendrltic tree. both in terms of branching and in numbers of spines. correlates well with increasing numbers 01 synapxs measured by electron microscopy.“,” Ho&ever, apart from a few Golgi studies in the perturbed developing hippocampus including after X-ray irradiation. deafferentation. alcohol treatment and in mutant animals. very little information is available about changes in the intrinsic anatomy of this brain region in the developing thyroid-deficient rat.‘.“. 6.x Recently. we have reported an irreversible Impairmcnt of the development of the whole hippocampal structure. including a deficit in final cell number in hypothyroid rats.” Further studies indicated that this reduction in the growth of the hypothyroid hippocampus is related to a retardation of cell migration towards dentate gyrus, rather than to cKcct\ on the replication of intrinsic cells.‘* In the present paper ue wanted to show that in thyroid deficient rats the maturation of both granule cells and pyramidal cells is impaired: however the effect on the *This and the accompanying paper are dedicated to Prof. Ja(que\ Leprand. who died 24 November 19X5.

pyramidal cells depended on the position of the cells in the ,4mmon‘\ horn of the hippocampu\.

Anhd\

Offspring of Wistar rats born on the same day wcrc pooled and randomly distrihutcd on the da> of hlrth IntO nursing famillcs of X rat pup5 per lactating mother The normal length ofgestation ma!, carefull! vcrlficd and lhe da! of birth was taken ah da) 0. The haung rat\ ucr-e ma& hypothyroid hy treating the dams dall> alth 50 mg prop>lthiouracil hq gastric intuhation from da) IX 01 pe\t.ltlon until the pups ucrc killed.” In addition a group of hypothyroid young rats were given rrplacemcnt treatment by daily subcutaneous injection of thyroxine li,r 7 or 4 days before the) were sacrificed. The phyrlologlcal corrective doses of thyroxine used were the same :,\I descrlhed hy Rabit! (‘I crl.“

The normal, hypothyroid and hlpothyrold pups given replacement thyroxine treatment were sacr~ticed at 6 or IO days after hlrth The bram was rapldly dIssected and immersed overnight in Golgi Cox tixatikc. Next da\ the brain was transferred to fresh fixative and stored ior 2 months in the dark at I4 C. The fixed tissue ua\ cmhedded in celloidln. The \ectlons (I SO Atrn thick) were prepared and treated accordmg to the Ciolgl Cox procedure.” The hippocampus was sectloned in the horizontal plane so that observations could be made on the complete dendrttlc tree of pyramidal cells (Fig. lb). All measurements w’ere made in midseptotemporal sectmns of the hlppocampus (Fig. I )_ The analy?es \%ere made at the same lebel throughout the different ages and treatment groups. .The selection of appropriate section< 01 comparable horizontal levels uas made hy counting the number of sections from the dorsal surface and also bq the shapes of the fimbria and of the hlppocampal tissure a\ guiding marker\

The tissue sections from a mmlmum of three rats were studied in each age group. The samples wcrc chosen from well-impregnated regions where cell individualit) was clearly maintained. Sections from the different ages and treatment groups were randomly distributed before the quantitative study to minimize possible subjective bias. The measurements on the granule cells of the dentate gyrus and on the pyramidal cells of the Ammon’s horn were carried out in IO-day-old and in h- and IO-day-old rats. respectively. The entlre cells were traced with the help of a x 5x5 camera lucida attached to a microscope at magniticatlon. The total number of branching points on the dendritic tree of at least 10 granule cells from both limbs of the granule cell layer were counted for each rat The Ammon‘s horn was divided into four areas, CAI. CAZ. (‘A3 and CA4. depending on the morphological features of the pyramidal cells,‘4 and at least 5 pyramidal cells were traced from each hippocampal area of an individual rat. The different measurements related to the growth of these cells were made by using a digitizing tablet connected to a microcomputer as shown in Fig. 2. First, the global number of branching points was counted on both apical and basal dendrites. and then the frequency distribution of these branching points was determined along the symmetry axis of the cell. The measurements provided a rough estimation of the shape of the dendritic field of each cell. Measurements

were also made of the total height of the apical dendritic tree and the volume of the pyramidal cell body. The cell volume was estimated from the cross-sectional area of at least 10 cells per hippocampal region. It was assumed that the possible shrinkage induced by the tixation was the same m normal and hypothyroid animals and that the experimental treatment had no significant effect on the Golgi COY impregnation procedure.

The results were analysed statistically, either by analysis of variance with one-way classification (treatment) or by Student’s f-test.” With analysis of variance, the significance of differences between the mean values of various groups were analysed by Duncan’s multiple range test.’ The results of the frequency distribution of branching points were compared using the chi-squared test. RESULTS Development

of’ granule

cells

In the 6-day-old rats. the arborization of the granule cell dendritic tree was not sufficiently developed to allow reasonable quantitation of the branching points, therefore estimates were made only on IO-day-old animals. At this age, the number of branching points per granule cell was 30.6 k 2.0 (mean + SEM) for normal, 19.6 & 0.5 for hypothyroid and 32.1 k 0.5 for hypothyroid rats given physiological doses of thyroxine for 2 days before sacrifice. There was a marked reduction in the development of the dendritic arborization of granule cells of the dentate gyrus in experimental hypothyroidism. However, this feature of dendritic maturation was restored to normal after 2 days of thyroxine replacement (Fig. 3). Derekopment

of pyramidal

cells

The general appearance of the pyramidal cells at the light microscope level was similar to that described previously.‘.” “)J In normal rats. the

pyramidal ceils were about 200 250~~11~II? ~c. ~\lth an elongated triangular ccl1 body (15 71 gm). The apical dendrites were of large diameter ~lhcn Ica\mg the perikarya. but rapidly became thinner ;md rn~rr~: branched. The basal dendrites were more numerous. thinner and shorter in length than apical dendrites (Fig. 4a). In hypothyroid rats. the p~rax~~~dal ccl1 appeared LO have a smaller cell hod> $!nc! LLit’\< branched dendritic tree than III controls i t:ig. W. These qualitative morphological ti-ature> of- p!~-amidal cells seem to be restored to normal when hypothyroid rats are pivcn physiological ticks 01‘ thyroxine (Fig. 4~). Various quantitative morphometric measuremcnt~ were also made to elucidate the effect of thyroid hormone deficiency on the growth of pyramldal cell in well defined regions of the Ammon’s horn (Figs 5---g). The study was restricted to 6- and IO-day-old rats. because at these ages it was easy to observe and to trace entire pyramidal cells (Figs 1 and 2). In 14day and older animals, the impregnation of cells was markedly increased, and under the experimental conditions employed it was not possible to recognize ulth certainty all the dendrites belonging to one single cell. Volumes qf‘ the pyramidul wll hodics. In 6-day-old normal rats, the volumes of pyramidal perikarya seemed to be larger in the CA3 and CA4 arcas than those of the CAI and CA2 regions (Fig. 5~1). During the next 4 days the size of cell bodies increased markedly in the CA3 and CA4 areas, but relatively more so In the CA2 region. As a result. in the IO-day-old CA2-4 regions the cell volumes became twice as large as in the CA1 region (Fig. 5b). In the 6-day-old hypothyroid rats the volumes of pyramidal cell bodies were not significantly different from controls (Fig. 5a). Thereafter the developmental increase in areas CA24 was less pronounced. resulting In significantly smaller volumes of pyramidal perikarya in the CA24 regions in IO-day-old thyroid-deficient rats (Fig. 5b). Administration of physiological doses of thyroxine for 4 days restored the devclopmentai deficit completely in the CA4 area. bul only partially in the CA2 and CA3 regions of‘ the hypothyroid rata (Fig. 5b). ,Yumhc~r of branching poinrs otl rho apicrri dcndriflc~ tree ofpyramidal cel1.v. In normal rats, the pyramidal cells of the CA1 area displayed less branched drndritic trees than did the cells of the CA3 4 areas (Fig. 6). In this respect the findings were verb similar to those on the volumes of cell bodies (Fig. 5). However, while perikaryon volumes between 6 and IO days markedly increased. the branching of the apical dendritic trees did not significantly change during this period (Figs 5 and 6). Thyroid deficiency resulted in less developed dendrites. with about a 30% reduction in both 6- and IO-day-old rats in the number of branching points on apical dendritlc trees in all areas of the Ammon’s horn (Fig. 6). The number of branching points rapidly increased on the pyramidal cells of hypothyroid rats given physm-

1219

Thyroid

number branchtng

state and development

1’71 __

of the hippo~inlpLis

of

points

,

height apical

frequency distribution apical

basal

\-

points

along

cell

cell

the

dendri

of the

branching

volume

of the

tic

tree

axis

of the

body

Fig. 2. Description of the different measurements performed IIn pyramidal

Fig. 3 Camera lucida drawings of Golgi Cux impregnated granule cells of the dentate gyrub in IO-da)-<)ld (:I) normal (N). th) hypothyroid (H). and (c) hypothyroid rdt glren replacement thyr
logical doses of thyroxine for 2 or 4 days. The effect of thyroxine was relatively more marked on the larger and more branched pyramidal cells of the CA4 area than of the CAI area; however, in all the regions of IO-day-old thyroxine-treated rats the number of branching points was significantly greater than that of both hypothyroid animals and controls (Fig. 6).

.VwrItw c!f’hronchitlg

points

011 the hasul riendritr~s

ceils of Ammon’s horn have numerous. fine and branched basal dendrites (Fig. 41. There were twice as many branching point\ on the basal dendrites when compared with those on the apical dendrites of the normal pyramldal tolls (Figs 6 and 7). Also. the difference between CA I and <‘A4 areas was much greater for basal dendrites than for apical dendrites. Pyramidal ceils of the CA4 area at 6 days had about double the number of branching points as did the cells of the CAI area. However. the difference between the CAI and CA4 areas became less in IO-day-old rats. Thyroid dcticiency resulted in a marked reduction in the numhcl- of branching points of pyramidal cells of the py~midd

c,ells. Pyramidal

throughout

Ammon’s

greater in the CA3

horn.

The

&‘cct

was much

area than in the CA1 arca (Fig.

7). Administration of physiological amounts of thyroxine for 2 or 4 days before sacrifice increased the number of branching points in ll~pothyroid rats. In IO-day-old hypothyroid rats the cfrect was relatively more marked. and in these animals after thyroxine replacement the number of branching points increased rapidly and reached a signiticantly higher value than in controls (Fig. 7). Heiaqhts of rite qx’cd ~~(~~~~jti(,trwz. In all areas of Ammon’s horn the heights of the apical dendritic trees of pyramidal cells varied bctwccn I47 and 179 1-1 m according to the area of the Amman’s horn. and did not change between 6 and IO days of age (mean values & SEM were I64 k 4 at 6 days and 165 i_ 7 at 10 days). Similar apparent consistency in the heights of the apical dendritic trees throughout the Amman’s horn was also found in hypothyroid animals. However. the values in thyroid-deficient rats varied between I 16 and I57 ii m according lo the area of the Amman’s horn. which wc‘rc significantly lower

b)

N

CA3-4

Fig. 4. Camera Iucida drawings of GolgiXox impregnated pyramidal cells of Ammon’s horn from areas CAI-2 and CA34 in lo-day-old (a) normal (N), (b) hypothyroid (I-I), and (c) hypothyroid rat given replacement thyroxine treatment during the 2 days preceding sacrifice (T).

(by about 15%) than the control values (mean values + SEM were 142 + 4 at 6 days and 142 &-6 at 10 days). Frequency distribution of dendritic branching points along the axis of the cell. The above observations have

indicated continuous changes in the growth of the dendritic tree of the pyramidal cells in the different areas of the Ammon’s horn. These developmenta changes in the dendritic pattern in normal and hypothyroid rats, and in thyroid-deficient rats given thyroxine replacement can be visualized better from the frequency distribution of branching points given in Fig. 8. For the sake of simplicity, on this figure the data for the areas CA1 and CA2 on the one hand and for CA3 and CA4 on the other were pooled. The expression of the results in this manner reduces the differences between the CA1 and CA4 areas (Figs 6 and 7), but, due to the increase in the number of observations in each group, would make comparison between the two groups more reliable. In 6-day-old normal rats, the pyramidal cells in the CA34 group had relatively well-developed apical and basal dendritic arborization (Fig. 8b, N). On the other hand, the pyramidal cells in the CAl-2 areas had very few branching points on basal dendrites or

on the distal part of apical dendrites

(Fig. 8a, NJ. Between 6 and 10 days very little alteration was observed in the general appearance of’ the dendritic field in the CA3-4 areas (compare Fig. 8b, N with 8d, N), but the shape of the dendritic field in the CAI-2 areas at 10 days started to resemble that of 6-day-old pyramidal cells of the CA334 areas (compare Fig. 8c, N with 8b, N). These observations suggest a marked delay in maturation of CA l-2 cells in comparison with the pyramidal cells of the CA334 areas. Experimental hypothyroidism did not markedly alter the qualitative shape of the dendritic field in the CAl-2

and CA3-4 areas from that already described

in developing normal rats (Fig. 8; H). However, a quantitatively significant reduction in branching points was observed at all levels, and in particular the branching points on basal dendrites and the arborization of distal parts of the apical dendrites were found to be markedly affected (Fig. 8, H). The dendritic arborization of pyramidal cells was greatly altered in hypothyroid rats after thyroxine administration (compare Fig. 8. H with 8, 2 and 8, 4). In the CAl-2 areas of the 6-day-old animals 2 days of hormone treatment induced the formation of new

Thyroid o)

state and development

6 df3ys _.*I

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0 i

~~:~~ ______

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,’

SAL

Gil

______

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2

b) 10 days C?

‘\ ‘\

r3

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FAl+ __ __ __ , ____ _-__- ---~~~~ ____-___.-_- ____- CA? __

N

L

2

H

Fig 5 Cell hody volume of the pyramidal cells of the hippocrmpus. Effects of thyroid state and variations with Amman’s horn area. (a) at 6 days. (b) at IO days. N. normal animals: H. hypothyroid animals; 2,4, hypothyroid animals rccerv,ing thyroxine. respectively. during the 2 or 4 days precedrng sacriticc: CAI 4. areas of Ammon’s horn. Each column is the mean of 3 experiments with the SEM indrcated by the bar. For each area, one-way analysis of variance (treatment): 6 days (CA1 to CA4: not significant); (0 days (CAI: not significant: CA2: P ~0.01; CA3 and CA4: P < 0.05). Duncan‘s test: significant difference with normal, IO days (CA2 and CA3: H. 2 and 4; CA4: H and 2): ctgniticant difference with hypothyroid, IO days (CA2 to CA4: N).

branches. first on the proximal part of the apical dendrrtes (compare Fig. 8a. 2 with 8a, H) and then on the distal part (Fig. 8a, 4). A similar increase in branching points was observed in the CA34 areas of hypothyroid rats after thyroxine replacement. Howcvcr. in the CA3 4 areas the effect was much more pronounced than in the GAIL2 areas (compare Fig. Sa. 2 with Xb, 3 and 4). In the CAI-2 areas of IO-day-old rats. thyroxine induced a general increase in the number of branching points without affecting the shape of the dendritic field (Fig. 8c, 2 and 4). On the c>tlisr hand. the effects of the hormone on the CA3 4 areas were more striking, showing an approximate doubling in the number of dendritic branching points at the basal level and about a 3-fold increase on the proximal parts of the apical tree (compare F:lg. ‘id. 7 with Xd, H). When the hormone treatment U:IS c,ontinued for 4 days a significant increase in the numbc~- of branching points could also be seen at more distal parts of the apical dendritic tree (compare FIN. Xd. 4 with Xd. 2). DISCl_‘SSION

Previous hippocampus

studies indicated

on

the a

development

complex

of

spatiotemporal

the

of the hippocampus

1223

relationship between the time of origin and subsequent differentiation of granule and pyramtdal ,cells,:.~ ( 1: 14.:l,lJ.lo.~l.lh In general. the granule cells nearest the molecular layer are formed earlier than those towards the hilus. while the differentiation of granule cells starts earlier in the suprapyramidal blade of the dentate gyrus than in the infrapyramidal blade. On the other hand. the pyramidal cells are generated in an “inside-out” pattern. that ix the deeper cells are formed before the more superticial cells in the pyramidal layer. and during maturation the apical dendrites of the pyramidal cells arc formed earlier than the basal dendrites. In the present study. even though the maturation of the dendritic trees of hippocampal cells. measured in terms ~~I‘ the number of branching points. were estimated during a very short period of development. the overall findings were consistent with those described prcviously,!,l? lY.?3.?jHowever. the growth of the pyramidal cells in different parts of the Amman’s horn was not uniform (Fig. 8). Between 6 and IO days after birth, the volumes of the perikarya and number of branching points on apical and basal dendrites Increased markedly in the CA24 areas. but on the other hand these parameters showed relatively littlc variation in the CA1 area (Figs 5 OX).Closer cxamination in individual areas of the Amman‘s horn indicated a gradient of progressively prcater maturation of the pyramidal cells from the <‘,AI to the a)

6 days 50

0I

b) 10 days

Fig. 6. Number of branching points on apical dcndrrtes of pyramidal cells of the hippocampus. Effects of thyrord state and variations with Ammon’s horn area (a) at 6 days. (b) at 10 days. N. normal animals: H. hypothyrotd anrmals. 2.4~ hypothyroid animal receiving thyroxrne respectively during the 2 or 4 days preceding sacrifice; CAI 4, areas 01 Ammon’s horn. Each column is the mean of 3 expenments with the SEM indicated by the bar. For each area. one-way analysis of variance (treatment): h days (CA): P < 0.05. CA2: P < 0.01: CA3: not significant: CA4. P e 0 05): IO days (CA1 to CA4: P < 0.01). Duncan’s test: signiticant difference with normal. 6 days (CA2 and CA4: HI. IO days (CAI: H and 2; CA2 to CA4; H. 2 and 4): signtticant difference with hypothyroid. 6 days (CA I : 2 and 4: CA2 N. 2 and 4: CA4: N and 2). IO days (CA I to C.44: Y. 2 and 4)

cl]

b days

C’A4 area

(Figs

morphologically

5--7).

It uould

different

of these

CAL ,’ o-

b) 10 days

N

H

2

L

Fig. 7. Number of branching points on basal dendrites of pyramidal cells of the hippocampus. Effects of thyroid state and variations with Ammon’s horn area (a) at 6 days. (b) at 10 days. N, normal animals; H. hypothyroid animals; 2.4, hypothyroid animals receiving thyroxine, respectively, during the 2 or 4 days preceding sacrifice; CA 14. areas of Ammon’s horn. Each column is the mean of 3 experiments with the SEM indicated by the bar. For each area, one-way analysis of variance (treatment): 6 days and 10 days (CA1 to CA4: P -c0.01). Duncan’s test: significant difference with normal 6 days (CA1 to CA3: H; CA4: H. 2 and 4), IO days (CAI: H and 2; CA3 and CA4: H, 2 and 4); significant difference with hypothyroid, 6 and 10 days (CA1 to CA4: N. 2 and 4).

appe~

itl;li

uw

cellx I(! x UXYI~ horn observed bq i r’rcntc c!-

areas of the Ammon’s No!’ may relate to differences

50-

also

pyramidal

m maturatlc~r~

p‘tticril.,

cells.

From early studies. on !he basis of qu,lnt~t;lti\~. morphological measurements. including the C~m~~un~ of neuropil relative to the space occupied by PII-amidal cell bodies. the number of nerve fibr,:s per LJIII~ area. and the length, densit! and amount Cit’branching of dendrites. Eayrs”’ ha\ suggested that there is about an 80% reduction In the probablllti oi neuronal interactions in the hypothyroid sensor]motor cortex. More direct quantitative estimations on synaptogenesis in the visual cortex contirmed that there was such a severe reduction in neuronal connections in hypothyroid rats.’ Similarly. .! marked delay in the maturation of the Purkinje ceil dendrltlc tree and a reduction in synaptogencsis in h~th the molecular and the internal granular layers have also been reported in the cerebellum of thyroid-deficient rars.“.‘“.“~“’ A significant reduction in the ,trborl/ation of pyramidal and granule cell dendrltic fields observed in the present study IS consistent ulth the earlier findings (Figs 5-7). Moreover. the administration of physiological doses of thyroxine confirmed that the areas where the pyramidal cell maturation was most impaired by thyroid defkienq were aiso the most sensitive to the hormone treatment. These observations were in agreement with the concept that thyroid hormone is important in the chtabhshment of the CAI to CA4 gradient of pyramidal

30branching points

Fig. 8. Frequency distribution of branching points along the cell axis of pyramidal cells of thr hippocampus. Effect of thyroid state and variation with Ammon’s horn area. (a) CA1 -2 areas at 6 days. (b) CA3-4 areas at 6 days, (c) CAI -2 areas at 10 days, (d) CA34 areas at IO days. N. normal animals; H, hypothyroid animals; 2,4, hypothyroid animals receiving thyroxine respectively during the 2 or 4 days preceding sacrifice. The width of the histograms is proportional to the mean number of branching points counted at the corresponding level of the dendritic tree. A11 frequency distributions were found significantly different according to the X’ test (P -c0.01)

Thyrord cell differentiation. thyroid

Our

tindmgs

state and daelopment

also indicated

deficiency leads to distortions

synchronized different

shifts

regions

in the relative

rather

that than

development

of the hippocampus

(Fig.

of

8). The

Furthermore. reduction

the observations in

aith

maturation

and maturation the asynchronous

of

pyramidal

granule cells of the dentate gyrus project their axons

would result in a major

(mossy fibrcs) on the apical arborizations

relationships

and CA4 pyramidal

carried out on the development turbcd

cerebellum controlled

that

arborization

by interactions

types of cells which establish ccl1 dcndritcs

of normal

have shown

gcncsis of the dcndritic is tightly

of Purkinjc

towards

I and 6). This

in the developing

In the hippocampus. the Ammon’s

horn

prcclsc Icvel\ 01‘ the dendritic

tree.”

possible that the rclativcly

cells

with all the other

(for rcfercnccs see Refs

ncrvoub system.

and pcr-

the morpho-

contacts with Purkinje

is probably a general phenomenon inputs

of the CA3

cells.” Also. the detailed stud&

the different

morphological of

shown

5 7).

and

cells in

granule

ctTect on the

of the cerebral

cortex

and the btochemical matur-

neurotransmitter

specific proteins

(Figs

in spatiotcmporal

A differential

development

and the hippocampus.”

systems”

D1, D2 and D3.”

in experimental

x4 and

hrxn-

has aIrcad!

hypothyroidism.

It

hccn

15 sup-

gested that such distortions,

rather than synchronixd shifts in normal developmental relationships. may he instrumental

arc exerted at

pairments

Thercl’ore

thyroidism.

it is

animals.

of granule alteration in

cells

distortion

between pyramidal

thyroid-deficient

ation

also suggest that the

number

cells, together the

I72

of the hlppocampuh

in causing that

are often

the lasting

functional

seen in congenital

mlhype-

more scvcre effect on the

CA3 and CA4 arcas of the Ammon’s

horn (Figs

5- 7)

may bc related to ;I decrease

from ;I marked reduction cdl\ in the dcntatc pyrus

in interaction, resulting in the number of granule of hypothyroid

rats.““‘

REFERENCES

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