Glutamate uptake, glutamate decarboxylase and choline acetyltransferase in subcortical areas after sensorimotor cortical ablations in the cat

10, pp. 287-293, 1983.e Ankho International. Printed in the

Vol.

Brain Research Bulletin,

U.S.A.

Glutamate Uptake, Glutamate Decarboxylase and Choline Acetyltransferase in Subcortical Areas After Sensorimotor Cortical Ablations in the Cat ANDRk Dhpartement

NIEOULLON

de Neurophysiologie

gP&rale-INP-CNRS-B.P. Received

NIEOULLON,

AND NICOLE

A. AND N. DUSTICIER.

Glutamate ablations

22 September

DUSTICIER 71, 13277 Marseille,

Cedex 9 France

1982

uptake, glutamate decarboxylase and choline in the cat. BRAIN RES BULL lO(3) 287-293,

acetyltransferase

in

1983.-High affinity uptake (HAGU), glutamate decarboxylase (GAD) and choline acetyltransferase (CAT) activities were measured from subcortical nuclei in the cat brain after ipsilateral ablation of the sensorimotor cortex. Results showed a drop in HAGU in all the structures assayed except the subthalamic nucleus. These changes in HAGU are generally accompanied by a decrease in GAD while CAT is unaffected. However, in the red nucleus the drop in HAGU is concomitant to an increase in GAD and CAT. In the subthalamic nucleus HAGU and CAT are increased while GAD is decreased. These

subcortical glutamate

areas after sensorimotor

cortical

results are consistent with the concept that most corticofugal tibres to subcortical structures use glutamate as their neurotransmitter. Results concerning GAD suggest that GABAergic subcortical neurons are under a cortical influence. This influence seems to be weak on cholinergic neurons. Glutamate uptake

THE cerebral cal structures

Glutamate decarboxylase

cortex exerts a facilitatory involved in sensorimotor

Choline acetyltransferase

Cortical lesion

transmitter systems in the same subcortical nucleus. Lesions of sensorimotor cortical areas have been performed in adult cats and the activity of markers of glutatnatergic, GABAergic and cholinergic systems measured 8 to 10 days after surgery in samples microdissected from different subcortical nuclei. High affinity glutamate uptake (HAGU), glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) activities have been measured as specific markers of these neuronal systems. Since corticofugal projections are mainly ipsilateral we have restricted our study of the effects of unilateral cortical lesions on subcortical structures localized in the side ipsilateral to the lesion. Results confirm glutamic acid (Glu) could be involved in the corticofugal transmission and are compared to previous similar studies in rats and cats performed in the same brain areas.

action on subcortiintegration. The

physiological role of the cortical projection to these structures is however in debate. The motor cortex is commonly considered to send an efference copy of the motor command to subcortical structures involved in the central programming of the motor task, such as the basal ganglia, the ventrolateral thalamus and the precerebellar pontine and reticular nuclei. This cortical output may control the activity of the structures which contribute to the extrapyramidal pathways (see [6,16]). The anatomical organization of cortical projections to subcortical structures is well-known. Sensorimotor cortical areas are generally thought to play the most important role. The majority of the corticofugal tibres come from this region. A few of these reach the spinal cord [31]. Our knowledge of the control exerted by the cerebral cortex on subcortical structures results from electrophysiological studies which emphasize a primary excitatory action (see [ 14,231). The present study was undertaken to investigate in the cat the role of cerebral sensorimotor areas on the activity of neurotransmitters in subcortical structures. Lesions of the cerebral cortex performed in the rat have shown that the activity of some basal ganglia neurotransmitters is modified [4,5, 8, 11, 13, 18,27, 321. This has led to the recent suggestion that cortico-striatal tibres are glutamatergic [5,18]. Our study differs from other studies in that we have mapped the effect of cortical ablation on the activity of three neuro-

METHOD

Surgery and Dissection of Samples The pericruciate cortex of one side in adult cats was removed by suction under deep halothane anaesthesia. The surgical ablation was localized to the anterior, posterior and lateral sigmoid gyrus and to the coronal gyrus. The deeper part of the cruciate sulcus was also completely removed as well as a part of the proreate gyrus of the frontal cortex. The ablation concerned the whole cytoarchitectonic areas 4, 3, 1, 2, 5 and part of area 6 (Fig. 1). During the survival period no major neurological deficit was observed except a loss of the tactile placing reaction of the limbs in the side

287

288

FIG. 1. Frontal view of the cat brain. The hatched zone indicates the limits of the cortical Ie~~n It mainly involves the sensorimotor area of the cerebral cortex on one Gde. cr.: cr-uciatc \II!CII\. car.: coronalis sulcus.

contralateral to the lesion. After an 8 to 10 day survival period determined as the optimal time to get maximal changes in neurotransmitter activities after brain lesions (see 120,211) animals were reanaesthetized and their brain quickly removed. For HAGU determination large pieces of brain containing the structures for analysis were immediately placed in an ice-cold 0.32 M sucrose solution and rapidly dissected using a cryostat (Leitz microtome) at a temperature of -4°C. In the experiments where GAD or CAT activities were to be estimated the fresh brains were frozen on dry ice and placed on the cryostat set at -10°C after quickly removing them from the skull. Serial section 500 pm in thickness were made and microdiscs of tissue were punched out from serial slices on the side ipsilateral to the cortical lesion with a special stainless steel tube 0.8 mm in diameter sharpened at the extremity according to the technique of Palkovits [22] as previously described [20]. The remaining part of the brain containing the frontal part of the cerebral cortex was placed in 10% formalin solution for subsequent careful examination of the lesioned area. Immediately after dissection tissue samples (0.3 to 0.5 mg) were placed in minitubes containing either 15 ~10.32 M isotonic sucrose for HAGU determination or 50 ~1 of an ice-cold 10 mM,sodium phosphate buffer tpH 7) containing 10 mM ,&mercaptoethanol for enzyme assays. In that last case Triton X-100 0.2% was~added to induce a total release of enzyme activity.

High afftnity glutamate uptake was measured according to the technique of Storm-Mathisen 1291 previously described with the main characteristics of the uptake assay (121. Homogenates were made in 0.32 M sucrose solution with a micro-Potter homogeneizer to produce suspensions containing nerve endings. The entire homogenate was diluted in 300 ~1 of an artificial cerebrospinal fluid (CSF: 140 mM NaCI; 5 mM KCl; I.2 mM CaCI,; I.2 mM MgSO*; I5 mM NaP buffer pH 7.4 and S mM glucose). High affinity transport of glutamate was assayed on 200 ~1 of the suspension and the remaining was used to determine the protein content of each sample. The suspension containing nerve ending particles was incubated for 3 min at 25°C with L(GJH) glutamic acid (specific activity 35 Ci/mmol) at a final concentration of 1 PM after a 5 min preincubation period. The reaction was stopped by centrifugation (5 min. 10.000 g). Pellets were washed twice and radioactivity was estimated after dissolution of the pellet in 100 +I of water containing Triton X-100 5%. Blank values were obtained from samples kept at 0°C. In these experimental conditions the uptake of Glu was shown to be absolutely Na’-dependent.

Glutamic acid decarboxylase activity was assayed by the CO, trapping procedure of Albers and Brady ]I] on 10 ~1 of homogenate prepared by weak sonication. The reaction

NEUROTRANSMITTERS

AFTER CORTICAL

LESIONS TABLE

DISTRIBUTION

1

OF NEUROTRANSMITTER MARKERS IN SUBCORTICAL NON-OPERATED ANIMALS

Structure Basal ganglia caudate nucleus putamen subthalamic nucleus substantia nigra Thalamus nucleus ventralis I anteriornucleus ventralis lateralis area nucleus ventralis lateralis nucleus ventralis posterior lateral Mesencephalon red nucleus cerebral peduncle

STRUCTURES

HAGU

GAD

CAT

nmoles/min/g protein

nmoles/hr/mg protein

nmoles/hr/mg protein

20.7 17.2 5.9 4.5

2 ? ‘L

1.8 (28) 1.3 (16) 0.4 (19) 0.6 (23)

32.7 + 2.9 (15)

109.9 140.8 190.7 678.5

+ 23.1 (33) + 19.7 (23) 2 20.6 (44) + 248.4 (70)

by adding

10 ~1 of a mixture

69.4 101.3 10.7 8.6

t f 2 +

5.9 9.2 2.1 2.9

(16) (16) (14) (57)

84.9 _t 10.1 (51)

32.3 ? 4.2 (18)

15.4 * 1.3 (19)

156.2 +

15.2 (44)

14.9 r 1.8 (15)

9.6 ? 1.1 (12)

136.4 2

15.4 (63)

17.8 + 2.2 (14)

1.5 2 0.2 (24) 0.6 + 0.1 (9)

90.9 + 23.4 +

10.4 (40) 2.7 (10)

13.4 * 5.9 (11) 5.5 + 1.2 (4)

Results are mean 2 SD. of (N) samples obtained in 7 to 10 cats. HAGU=high GAD=glutamate decarboxylase; CAT=choline acetyltransferase.

was initiated

OF

containing

2. IO-*

M L-glutamate, 2. 10e4 M pyridoxal phosphate and 20 &i/ml L-1(14C) glutamic acid (specific activity 276 Ci/mmol). The reaction was made in 1.5 ml hermetic Eppendorf tube in which was placed a microtube containing a strip of Whatmann 3MM chromatographic paper impregnated with 5 ~1 of 1 M hyamine hydrowide. After a 20 min incubation at 37°C the reaction was stopped by injecting 1 M H,SO, (50 ~1) into the closed tube. Maximal absorption of (Y)-CO, on the hyamine impregnated strip was achieved by placing the reaction tube for 10 min at 60°C. The radioactivity retained on the paper was estimated by liquid scintillation spectrometry. Blanks were prepared by substituting 10 ~1 of buffer for the tissue homogenate.

Choline acetyltransferase activity was estimated by the method of Fonnum [7] using synthetic radioactive acetyl CoA (specific activity 59.5 Ci/mmol) as substrate and a liquid cation exchange to separate radiolabelled acetylcholine (ACh). Incubation was performed during 10 min at 37°C. The reaction was stopped by adding 100 ~1 of tetraphenylborate in ethyl-buthyl ketone (10 mg/ml). After shaking and centrifugation 50 ~1 of the organic upper layer was transfered into vials for the estimation of radioactivity. Blanks were prepared as for GAD assay. In the conditions of the assays the rate of Glu accumulation as well as the enzyme activities were shown to be proportional to the amount of tissue. Protein content of each assay was determined by the method of Lowry et al. [ 171 on an aliquot of the homogenate using bovine serum albumin as standard. Data

per

uptake;

min incubation time per gram of protein. GAD activity represents the number of nanomols (Y)-CO, or GABA formed per hour and per mg protein. CAT values illustrates the number of nanomols of (14C)-ACh formed per hour and per mg protein. Results are mean *S.D. of values obtained in N animals from different samples assayed in a given brain structure. Data obtained in lesioned animals either in the side ipsilateral to the cortical lesion or in the contralateral side are compared to those obtained in control unlesioned animals and statistically evaluated using Student’s two tailed t-test (p
Distribution of Neurotransmitter Sensorimotor Nuclei

Choline Acetyltransferase

HAGU is expressed as nanomols of Glu incorporated

affinity glutamate

Markers in Subcortical

HAGU, GAD and CAT activities measured in 9 brain structures in the cat show an uneven distribution. Table 1 presents the results. Neurotransmitter markers were detected in all areas considered even in pure white matter of the cerebral peduncle. The rate of Glu transport can be considered as a reliable index of glutamatergic activity although we have previously shown this rate is highly reduced in the conditions in which the dissection was performed at -4°C. We have shown in these experimental conditions Vmax was the only parameter affected by the refrigeration of the tissue with no change in the affinity constant K,[12]. Higher HAGU levels are measured in the thalamus and the striatum while other areas present low activity. Maximal GAD activity was measured in substantia nigra samples. Large standard deviation of the mean illustrate the GABAergic innervation of the nucleus is uneven within the structure. Caudal parts of substantia nigra present higher GAD levels. Other basal ganglia nuclei and thalamic struttures have similar GAD activity.

NIE(,UI.I.ON

Putan BASAL

calldate

Sub. thal.

Putamen BASAL

Sub6t. GANGLIA

VL

VL-VA

Red wcleus

nigra THALAMUS

FIG. 2. Effect of unilateral ablation of sensorimotor cortical areas on high affinity glutamate uptake (HAGU) in subcortical structures on the side ipsilateral to the lesion. Results are expressed as a percentage of the HAGU level measured in the same structures of control animals (100%). Control levels of HAGU are given in Table I. Sub. thal.: subthalamic nucleus; Subst. nigra: substantia nigra; VL: nucleus ventralis lateralis; VL-VA: area of nucleus ventralis lateralis and of nucleus ventralis anterior. *piO.O2 when compared to control values (Student’s r-test), except for Sub. thal=p
CAT levels are maximal in the putamen nucleus and low in other structures. Effects of Cortical Ablations ofSensorimotor on HAGU

Pericruciate

THALAMUS

-

.

140.

and the caudate

AreuJ

A large decrease in HAGU was found in all the subcortical structures studied except the subthalamic nucleus 8 to 10 days after lesions of the sensorimotor areas of the cerebral cortex. HAGU is decreased from 35% to 57% of control values. Mean decrease is of 44%. Maximal changes are seen at the level of the ventrolateral thalamic nucleus (VL) and in a more rostra1 thalamic region which involves both the rostral VL and the nucleus ventralis anterior (VL-VA area). Results presented in Fig. 2 illustrate data only obtained from the lateral part of the substantia nigra and also represent mean values of HAGU decrease measured in different parts of the red nucleus since these two mesencephalic areas are not uniform. They do not present homogenous changes in respect of cortical lesions. Maximal changes in caudal parts of the red nucleus reaches 50% HAGU decrease (Fig. 5). The cortical ablation results in the subthalamic area in a significant 20.6% HAGU increase (p
GAD Subcortical

0utet.ngra GANGLIA

FlG. 3. Effect of unilateral ablation ol’sensorimotor cortical areas on glutamate decarboxylase (GAD) activit) in subconical structures on the side ipsilateral to the lesion. Results are expressed as in Fig. 2. Sub. thal.: subthalamic nucleus: Subst. nigra: substantia nigra: VPI.: nucleu\ ventralis posterior lateral: VL: nucleu\ ventralis lateralis: VI.-VA: nucleus ventrali later;llis-ventrali~ anlcrior. *I’.. 0.05.

C&e

slh IM. Putamen

Effects of Cortical

AND DUSTICIER

Ablation ofl

Level.~

The cortical ablation produces in the cat a decrease in GAD activity measured in the putamen, the subthalamic nucleus, the nucleus ventralis posterior lateral (VPL) and the VL thalamic nuclei (Fig. 3). This statistically significant~ decrease is of 22 to 25% of control values (mean value: -22.5%; p
BASAL

subst GAffiLIA

VPL

VL

VL.VA

Redmlc~

ngra THACAMUS

FIG. 4. Effect of unilateral ablation of \cn,orimotor area\ 01’the cerebral cortex on choline acetyltransferase (CAT) activity in hubcortical structures on the side ipsilateral lo the lesion. Results are expressed as in Fig. 2. Sub. thal.: subthalamic nucleus; Subst. nigra: substantia nigra: VPI.: nucleus ventralis posterior later&; VL: nucleus ventralis lateralis: VL-VA: nucleus ventralis lateralis-ventrali\ anterior. */>~,0.05.

mean GAD value after cortical lesion (

16%) is not significantly different to control levels. No change was observed in the caudate nucleus and the VL-VA thalamic area. Interestingly enough a significant GAD increase is measured in the red nucleus (+ 16%). This GAD increase is seen particularly in the most rostral third of the structure where GAD values are 141% of control levels (Fig. 5).

Cortical lesions have very little influence on CAT activity at a subcortical level (Fig. 4). No decrease is seen. CAT is significantly increased @
NEUROTRANSMITI’ERS

AFTER CORTICAL

LESIONS

291

t A3

I

‘I

A4

A!J

FIG. 5. Effects of unilateral ablation of sensorimotor areas of the cerebral cortex on high affinity glutamate uptake (HAGU), glutamate decarboxylase (GAD) and choline acetyltransferase (CAT) activities in the red nucleus of the cat ipsilateral to the lesioned cortex. Biochemical parameters were measured in samples from serial slices of the red nucleus 8 to 10 days after surgery in order to analyse the effects of cortical lesions on the rostro-caudal dist~bution of these markers in the red nucleus. A3, A4 and A5 are three brain stem sections cut in the frontal plane; the red nucleus is indicated with an arrow. The diagrams illustrate the activity of these markers for HAGU, GAD and CAT in the caudal part (A3), the medial part 1A4) and the rostra1 part (AS) of the red nucleus in control animals (0) and lesioned cats (0). Results are the

meanrtS.D. of data obtained in at least 6 animals. Significance of differences from corresponding control values: *p
The unilateral ablation of cortical senso~motor areas in the adult cat results after an 8 to 10 day survival period in changes of HAGU, GAD and CAT activities in some of the subcortical structures we examined. The majority of the nuclei studied show a large decrease in HAGU and a lesser but significant decrease in GAD while CAT levels are generally similar to control values. Previous studies in the rat have shown similar results. HAGU decrease after cortical lesion was first described in the striatum [2, 5, 181, in the substantia nigra [4] and in the thalamic area [8]. Similar observations have also been more recently performed in the cat caudate nucleus, thalamus, pons and red nucleus [33]. These observations have led to the suggestion that the cortico-striatal and co~ico-thalamic pathways are glutamatergic and this proposition was supported by both electrophysiological and biochemical results.

Striatal cells were shown to be activated by iontophoretic application of Glu which is sensitive to the gIut~atergic antagonist glutamic acid diethylester (281. Also other biochemical glutamatergic markers studied were shown to be reduced after cortical lesions. This is the case for Glu endogenous levels in both striatum and thalamic areas [2,8, 11, 13, 18, 331. Glu release is reduced from slices of cortically deafferented striatum [24,25] and increased in vivo under cortical stimulation in the rat 193. After cortical lesions in the rat, glutamatergic receptors in the striatum detected both by Glu binding studies [25] and iontophoretic application of Glu [19] develop supersensitivity. This would indicate that our HAGU marker is a reliable index for glutamatertic activity. A decrease in the level of HAGU after cortical lesions in the cat may suggest that Glu is a neurotr~smitter in corticofugal fibres to the caudate nucleus, putamen, substantia nigra, thalamic nuclei and red

292

NIEOtiL.I.0N

nucleus. The extent of the HAGU decrease after a restricted lesion of the cerebral cortex confirms the important influence that the sensorimotor areas exert in the control of these subcortical structures (see 114,161). The significant decrease in GAD activity in the putamen, the subthalamic nucleus, the substantia nigra and some thalamic areas after cortical lesions agrees with similar studies in the rat striatum, thalamus [S] and substantia nigra [27]. However other studies have reported that GAD striatal activity does not change after this lesion [l&27]. A decrease in GABA uptake in the same structures [4,8] and in striatal GABA turnover [32] indicates that the GABAergic activity in subcortical structures is probably depressed after suppression of their cortical afferences. Increase in GABA receptor binding in the substantia nigra reinforces this hypothesis [ 151. The fact that in our study GAD activity in the caudate nucleus is not affected by the lesion but results in a decrease in the putamen may explain the absence of changes in GABAergic markers reported in the rat striatum [2, 18, 271. This effect could be confined to the putaminal part of the striatum which in the rat is not clearly identifiable. The cholinergic activity in subcortical structures has been thought to be unaffected by the cortical lesion. CAT activity is not changed in the rat striatum and in the thalamic area after large ablations of the cerebral cortex [8, 18,27,30] and our results in the cat are in agreement with these reports. However, our results do not agree with those of Young et 01. [33] where a decrease in CAT activity is observed in the cat caudate nucleus and those of Wood rt al. [32] describing a decreased ACh turn-over in the rat striatum after cortical lesions. Since Glu was recently reported to activate ACh release from the rat striatum [26] one can consider that the cerebral cortex normally exerts a facilitatory influence on cholinergic activity in the striatum. This action is probably weak as cortical lesions do not influence either the CAT activity or ACh endogenous levels [ 11,271. in the red nucleus the decrease in HAGU is paralleled by an increase in GAD and CAT activities in the most rostra1 part of the structure. Similar results are obtained in the red nucleus after lesions of its other main afferent pathway

AND L)US’I‘IClt;,K

which originates in the cerebellum. We have recently shown that the unilateral lesion of the cerebellum induced an increase in rubral GAD activity [20] while CAT levels are decreased 1211. Since GAD activity wa4 demonstrated to he very sensitive to a kainic acid lesion of the red nucleus (Nieoullon, unpublished data) we suggest that GAD increase after both cortical and cerebellar lesions corresponds to ;tn activation of rubral GABAergic interneurons. The CAT increase observed after cortical ablation5 could reflecl :I presynaptic activation of cerebellorubral cholinergic fibres 12I 1. In the subthalamic nucleus the cortical lesion results in an increase in HAGU and CAT activities concomitant with ;t decrease in GAD levels. CAT increirse can represent :in :IC‘tivation of an afferent pathway to the subthalamic nucleus which uses ACh as a neurotransmittcr. Our results do not verify the existence of ;I direcl cortico-subthnlamic glutamatergic pathway in the cat. This pathway ha> been described by anatomical methods in monkeys [IO] although its presence has not been confirmed 131. The HAGC increase observed in our experiments could I-eprehent an indirect activation of glutamatergic fibres afferent to the subthalamic nucleus not originating in the sensorimotor areas of the cerebral cortex. In conclusion our study suggest\ that glutamatergic iictivity in subcortical structures is linked lo the presence of corticofugal fibres originating mainly in sensorimotor areas. The decrease in GAD activity observed in many wbcortical structures after cortical lesions could reflect 3 facilitator) influence of cortical sensorimotor ;treas on \ubcorti4 GABAergic neurons exerted, at least partly. by mean of corticofugal glutamatergic tibres. This does not seem to he the

case for the cholinergic

system.

ACKNOWI.blLXF.ML:tS

1S

‘lhe authors are grateful to Lydia Krrherian for her r\cellenl contribution to experiments on glutamate uptake and to Dr. C. Palmer who kindly revised the English form of the manuscript. ‘l‘hi, work was supported hy grants from INSERM (contrat lihre no. 81.60.20).

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