Chapter 12 The distribution and function of gamma-aminobutyric acid (GABA) in the superior colliculus

R.R. Mize, R.E. Marc and A.M. Sillito (Eds.) Progress in Braid Research, Vol. 90 B 1992 Elsevier Science Publishers B.V. All rights reserved

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CHAPTER 12

The distribution and function of gamma-aminobutyric acid ( GABA) in the superior colliculus Yasuhiro Okada Department of Physiology, School of Medicine, Kobe Uniuersity, Kusunoki-cho, Chuo-ku, Kobe 650, Japan

Introduction The superior colliculus (SC) plays an important role in the integration of visual, auditory and sensory-motor information, especially in relation to eye movements. GABA must be involved in the integrative action of the SC because the SC contains many GABAergic neurons and concentrations of GABA and GAD in the superficial grey layer (SGL) are the highest in the CNS. Here we report the fine distribution of GABA and GAD in the SC of different species and the dose-dependent excitatory and inhibitory biphasic action of GABA on neurotransmission in SGL of SC slices. GABA in the SC controls eye movements, especially saccades, and further regulates the activity of collicular neurons which suppresses the propagation of seizures. Long-term potentiation can be elicited in the SGL after tetanic stimulation applied to the optic nerve. It is argued that GABA may be involved in modulating the formation of LTP in SGL. This chapter reviews the evidence for these functional effects of GABA in the mammalian SC.

Fine distribution of GABA and localization of GABA-sensitive neurons in the superior colliculus Gamma-aminobutyric acid (GABA) is widely distributed in the nervous system of vertebrates and

invertebrates. As regards the regional distribution of GABA in the central nervous system (CNS), the superior colliculus (SC) contains a high amount of GABA (Okada et al., 1971). Histologically, the superior colliculus is characterized by cells and fibers that are organized in a laminated pattern. Laminar analysis of the distribution of GABA as well as glutamate decarboxylase (GAD), a GABA synthesizing enzyme, was performed within the SC of the rabbit (Okada, 1974, 1976a), cat (Kanno and Okada, 1988) and guinea pig (Arakawa and Okada, 1988) using microassay methods (Okada et al., 1976). The regional distribution of GABA and GAD activity obtained for each layer of the superior colliculus is summarized in Table 1. The distribution pattern of GABA within the SC was similar in each species studied. The highest level of GABA was found in the superficial gray layer (SGL) averaging 37-40 mmol/kg dry weight. The GABA levels in the optic and intermediate gray layers were each only half that of the concentration in the SGL. GABA content in the intermediate white, deep gray and deep white layers was lower than the concentration in the optic layer, ranging from 10-22 mmol/kg dry weight. GABA concentration of the whole SC was 22.9 mmol/kg dry weight in the rabbit, 29.0 in the cat, and 18.0 in the guinea pig. These GABA values based upon dry weight are in good agreement with those by wet weight (Okada et al., 1971) if the dry weight of the tissue is assumed to be 20-25% of the wet weight.

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TABLE 1 GAD activity and GABA levels in the layers of the superior colliculus of rabbit (Okada, 1974), cat (Kanno and Okada, 1988) and guinea pig (Arakawa and Okada, 1989) Rabbit SGL (U) (L) OL IG IW DG DW

GAD

GABA

239.4

43.6 f 2.0 34.8f 1.8 22.3f 0.6 22.1 f 0.5 17.7f0.5 19.1 f 0.5 17.1 f 0 . 4

108.8 95.5 85.3 82.4 72.1

-

Cat GABA

Guinea pig GABA

(U) 40.3 (L) 36.8 28.2 24.1 24.0 25.2 24.5

(U)37.4

(L) 23.4

15.5 15.0 10.8 13.1 10.9

GABA, mmol/kg dry; GAD, mmol produced GABA/kg dry/h; SGL, superficial gray layer ((U) upper half of SGL) ((L) lower half of SGL); OL, optic layer; IG, intermediate gray layer; IW, intermediate white layer; DG, deep gray layer; DW, deep white layer.

The SGL, which contained the highest level of GABA, was further dissected into 6 thin laminated layers (50-80 pm in width). Table 2 shows the GABA distribution within the SGL of the rabbit SC. The GABA concentration of the superficial half was in the range of 40-44 mmol/kg dry weight, while the GABA content in the deep layers was 26-35 mmol/kg. This was true for the cat and guinea pig as shown in Table 1. A dry weight level of GABA of 44 mmol/kg is the same as that in the substantia nigra (SN) and the medial forebrain bundle which have the highest TABLE 2 GABA concentrations within the superficial grey layer of the rabbit superior colliculus Dissected layer

mmol/kg (dry)

1 2 3 4 5 6

44.3 f 0.9 44.8 f 1 .O 40.7+2.2 34.5 f 1.6 33.3 f 1.7 26.4 f 1.3 2 1 . 0 i 1.5

OL

f S.E.M.

The dissected SGL was further cut into 6 thin laminated pieces (50-80 km width), and the GABA content in each tissue piece was determined.

amount of GABA in the mammalian brain (Okada et al., 1971; Okada, 1980). GAD activity parallels the GABA levels in each layer of the SC and is highest in the SGL, where the highest level of GABA was also found. The GAD activity of other layers ranged from 30 to 49% of that in the SGL. Thus the distribution of GAD activity in each layer agrees well with that of GABA. The SC receives a substantial input from the visual cortex and retina as well as from other nuclei in the brain stem (Lund and Lund, 1971; Sprague, 1975; Wurtz and Albano, 1980). Fibers from the retina and visual cortex terminate in the SGL and optic layers in an orderly and precise fashion. Physiological studies have revealed that both retina and cortex exert an early facilitation and later inhibition on collicular neurons (McIlwain and Field, 1971). The SC on one side also exerts an inhibition on the contralateral tectum. To investigate whether the large amount of GABA in the SGL is contained in the afferent fibers terminating in the SC or originates intrinsically within interneurons, three major inputs to the SC of the rabbit were destroyed. In one group, the left visual cortex was ablated; in another group, the left optic nerve was transected just behind the eyeball; in a third group, the SC commissure was cut by knife. The GABA level and GAD activity in the SGL were determined in each animal at 12 days after these surgical operations. No decrease in GABA content in the SGL was.found by comparison with that of unoperated controls as shown in Table 3. These results indicate that the GABA concentrated in the SGL is probably intrinsic to the layer and likely contained within interneurons in the SGL. Numerous histological and immunohistochemical studies have indicated the existence of GABAergic interneurons in the SGL (Mize et al., 1981, 1982; Mize, 1988). Cajal (1955) designated the upper SGL the “zone of horizontal cells” and the lower SGL the “zone of vertical fusiform cells”. Mize showed that 45% of the SGL neurons and 30% of the intermediate grey neurons in the cat SC are GABA-immunoreactive (Mize,

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1988). Electron microscopic studies have also shown that there exist many nerve terminals with flattened vesicles in the SGL of the rat (Lund, 1969; Lund and Lund, 1970, suggesting that GABAergic neurons also are located within the SGL-of this species. In this connection, it is to be noted that the secondary inhibition evoked from the optic tract and the visual cortex is mediated by a single mechanism intrinsic to the SGL, and that this mechanism is postsynaptic in nature (McIlwain and Fields, 1971). In the intracellular recording studies of SGL neurons (Takahashi et al., 1977; Takahashi and Ogawa, 19781, units exhibiting distinct inhibitory postsynaptic potentials (IPSP) elicited by optic nerve stimulation were mainly found in the upper and middle part of the SGL. Iontophoretic application of GABA (Kayama et al., 1980) readily depressed the unitary discharges of Ia cells (vertical fusiform cells in the zone of horizontal cells, Lund, 1969) and IVb cells (stellate cells) whereas I1 (pyriform cells) and IIIa cells (narrow field vertical cells) were GABA-insensitive. Cultured SGL neurons also have been reported to be GABA sensitive (Warton et al., 1990). These biochemical, morphological, and electrophysiological studies thus suggest that there are GABA sensitive neurons in the SGL and that the inhibition is mediated by interneurons within the SGL, although some of the GABA contained in the intermediate gray layer also originates in the nerve terminals of the nigro-tectal pathway

(Vincent et al., 1978; Dichiara et al., 1979; Chevalier et al., 1981; Karabelas et al., 1985). Excitatory and inhibitory effects of GABA on synaptic transmission in superior colliculus slices In in vivo studies, iontophoretic application of GABA and muscimol into the SC can depress the evoked discharge of SC neurons, an inhibition that is antagonized by bicuculline (Kayama et al., 1980, Hikosaka and Wurtz, 1985). However, in these studies, the concentration of GABA required to produce the effect was not determined. To investigate the dose-dependent action of GABA in SGL, we have used thin slices of the SC from the guinea pig and applied GABA and its agonists and antagonists to the perfusion medium in known concentrations (Arakawa and Okada, 1987, 1988). To prepare SC slices, tissue blocks of the SC were dissected out from the brainstem and cut parasagittally into slices of between 400 and 500 pm thickness as shown schematically in Fig. 1. The postsynaptic potential was recorded from the SGL after stimulation of the optic layer (OL). The postsynaptic potentials have been recorded previously from the surface of SC slices in horizontal thin sections after stimulation of the optic nerve (Kawai and Yamamoto, 1969; Okada and Saito, 1979). However, in such experiments, only two slices could be prepared from each animal. In the slice preparation used here, cutting the SC

TABLE 3 GABA concentrations in the SGL after denervation of main input pathways to SC of the rabbit Treatment

No. of animals

GABA conce'ntration (mmol/kg (dry)) right-SGL

left-SGL

No surgical operation (control) Ablation of right visual cortex Transection of left optic nerve Sections of superior collicular commissure

4 4 3 3

40.6 f 1.5 (20) 39.8 f 1.1 (20) 38.2 f 1.1 (18) 39.5 f 1.0 (18)

40.9 1.3 (20) 39.8 f 1.3 (20) 39.4 f 1.2 (20) 40.5 f 0.9 (18)

*

252

sagittally allowed us to produce 10 slices with a histologically homogeneous structure from one animal. Using this preparation, recording and stimulating sites within the laminated SC were easily visualized. The potentials elicited in the SGL after stimulation of the OL or optic nerve are composed of two responses, an early prepotential (Fig. 1C-f) and a late potential (Fig. 1C-s). The late component was reduced by high frequency stimulation and was completely blocked in Ca2+-free medium, although the early potential was not affected. The potentials were also recorded from slices which contained only the SGL and the OL, and repetitive extracellular unitary discharges were often superimposed on the negative field potential. These results indicate that the late negative field potential with high amplitude represents the postsynaptic potential (PSP), probably a potential representing population spikes. A

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Fig. 1. A schematic drawing of a sagittal slice of the superior colliculus (SC) showing the placement of the stimulating and recording electrodes. A. A block of the brainstem containing the superior and inferior colliculus. The superior colliculus was cut sagittally into half at the centre. Five to 6 slices were obtained from each SC. It is important that the slices must be cut at a slightly oblique angle using the fibre input of the optic nerve as a guide. Cross-section slices of the SC do not result in good recording of the PSP.B. The arrangement of the recording and stimulating electrodes. C-1. Two kinds of negative potentials in the control response. Note the earlier deflection (f) in the declining phase of the large potential(s). (2-2. 10 min after removal of Ca2+ from the standard medium, the large potential(s) was abolished but not the earlier response (f). The early response (deflection) can now be clearly seen. C-3. The recovery of the later potential 10 min after reintroduction of Ca2+ into the standard medium. In A and B. ON, optic nerve; SC, superior colliculus; IC, inferior colliculus; SG, superficial grey layer; OL, optic layer; IG, intermediate grey layer; IW, intermediate white layer; DG, deep grey layer; DW, deep white layer.

Fig. 2. Effects of GABA, muscimol, and ( - bbaclofen on the PSPs evoked in the SGL of SC slices after stimulation of 0L.A. (1) Indicates the PSPs before the bath application of GABA (a, 1 mM; b, 10 mM), muscimol (c, 10 pM; 100 pM) or (-1-baclofen (e, 1 pM), These conditions represent the control situation. (2) The PSPs recorded 10 min after the application of drugs. The PSPs were enhanced in both (a) and (c), while they were depressed in (b), (d) and (e). An early low presynaptic potential was not influenced in any of the cases. (3) Twenty minutes after removal of the drugs. Each PSP returned to the control level. A downward deflection indicates negativity. B. The dose-response curves of the effects of GABA (open circles), muscimol (filled circles), or ( - bbaclofen (filled triangles) on the amplitude of evoked PSPs. The changes in amplitude are expressed as changes compared to the original level taken as 100%. On the abscissa the concentrations of the drugs are expressed on a logarithmic scale. At the lower concentrations of GABA, up to 1 mM, the amplitude of the PSPs was augmented in a dose-dependent manner, while at concentrations greater than 1 mM the PSP amplitude was diminished in a dose-dependent manner. A similar tendency was observed with the application of muscimol. However only a decrease of the PSP was obtained with the application of ( - )-badofen. Each plot indicates the mean value f S.E.M. obtained from 5 slices. Asterisks indicate a significant difference from the control values (two-tailed 1-test; * P < 0.05, * * P < 0.01).

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Figure 2A shows the effect of GABA, muscimol, and (-)-badofen on the PSP amplitude evoked in the SGL. Bath application of GABA at a concentration of 1 mM enhanced the amplitude of the PSP. The amplitude returned to its initial level 20 min after the removal of GABA. Muscimol at 10 p M induced a similar increase in the PSP amplitude and again the PSP returned to its control level after muscimol was washed out. Figure 2B illustrates the dose-response curve of GABA, muscimol and (-)-baclofen on the PSP evoked in SGL. When GABA was applied in the concentration range between 100 p M and 1 mM the amplitude of the evoked PSP increased in a dose-dependent fashion and a maximum increase in the amplitude of 54.2% was observed at 1mM. A similar pattern was obtained with muscimol, a potent agonist for GABA, receptors, at concentrations between 0.1 and 10 pM. In this case, an 89.3% increase in the amplitude of the PSP was observed at a concentration of 10 pM. No enhancement of the amplitude of the PSP was observed when (-)-baclofen, a potent agonist for GABA receptors, was applied. . GABA at concentrations greater than 1 mM subsequently depressed the PSP in a dose-dependent manner and completely abolished it at 10 mM. Similarly, the PSP was depressed at concentrations of muscimol greater than 10 pM, and 0.1 p M ( - )-badofen, and it almost disappeared at 100 pM muscimol and 1 pM (-)-badofen. Thus GABA and muscimol showed dose-dependent biphasic excitatory and inhibitory effects on neurotransmission whereas ( - kbaclofen had only an inhibitory effect. Bicuculline is a specific antagonist for GABA, receptors. Bicuculline methiodide at concentrations greater than 10 p M elicited by itself a long-lasting negative wave following the wave of the PSP which was recorded in the standard medium. To test the effect of bicuculline methiodide on the response to GABA, we applied bicuculline methiodide at a concentration of 1 pM, which does not influence the PSP nor evoke the long-lasting negative wave. Figure 3 shows the

%

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150

0

10-6

10-5

10-4

10-3

10-2

M

Fig. 3. The effect of bicuculline methiodide (filled circle) at a concentration of 1 p M on the dose-response curve of GABA. In the presence of bicuculline methiodide, the dose-response curve of GABA (open circle) at a concentration greater than 1 p M was shifted to the right, and the excitatory effect of GABA at lower concentrations was markedly enhanced. Bic, bicuculline methiodide.

dose-response curve of GABA in the presence of bicuculline methiodide at 1 pM. The dose-response curve for GABA inhibition was shifted slightly to the right, while the excitatory effect of GABA at lower concentrations was markedly enhanced. It is interesting to note that both GABA and muscimol had a dual effect on neurotransmission in the SGL, i.e., excitation or inhibition depending upon their concentration. By contrast ( - )baclofen had only an inhibitory effect. Bicuculline, a specific antagonist for GABA, receptors, shifted the inhibitory dose-response curve of GABA to the right at GABA concentrations over 1 mM (Fig. 3). These results indicate that GABA, and GABA, receptors are involved in the inhibitory action of GABA in the SGL. GABA has been believed to function primarily as an inhibitory neurotransmitter in the CNS, although several reports have indicated the possibility of an excitatory action of GABA because GABA can cause cell depolarization in the hippocampus CA1 region of the guinea pig (Andersen et al., 19801, the guinea pig myenteric plexus ganglion (Charubini and North, 1984), the supraoptic nucleus (Ogata, 19871, the dorsal root

254

ganglion of the rat (Deschenes et al., 1976) and the cat (Gallagher et al., 19781, and the superior cervical ganglia of the cat (De Groat, 1970) and rat (Bowery and Brown, 1974). In addition, there are reports indicating that GABA has an excitatory effect on neurotransmission in the isolated frog tectum (Nistri and Sivilotti, 1985; Sivilotti and Nistri, 1989; Mazda et al., 1990). Concerning the mechanism of the excitatory effect of GABA in the SC slice reported here, at least three possibilities can be hypothesized. First, there could exist a network of GABAergic inhibitory interneurons which are depressed by GABA within the SGL. At lower concentrations of GABA, only those GABAergic inhibitory interneurons which possess classical GABA, receptors might be depressed. The postsynaptic neurons which give rise to the excitatory postsynaptic potential would then be free from tonic inhibition, and evoked PSPs could be facilitated by disinhibition. At higher concentrations of GABA, however, both the inhibitory interneurons and the postsynaptic neurons could be completely depressed. In fact, Lalley (1983, 1986) proposed this hypothesis for respiratory neurons of the pontine region concerned with inspiration and expiration during systemic infusion of (-)baclofen. However, this hypothesis cannot explain the remarkable enhancement of the excitatory effect of the PSP at lower concentrations of GABA during the application of bicuculline methiodide at a concentration of 1 pM. Moreover, it is unlikely that the GABAergic interneurons are more sensitive to GABA than the postsynaptic cell for eliciting the PSP. In the second possibility, excitatory neurotransmitter release from the afferent optic nerve fibers might be modified presynaptically by GABAergic fibers terminating on the endings of the optic nerve fibers which would enhance the release of the excitatory transmitter used by the retinal afferents (probably glutamate). At lower concentrations of GABA, the presynaptic GABA receptors would be affected and release of the excitatory transmitter from the optic nerve terminal would be increas-

ed. At higher concentrations of GABA, the postsynaptic GABA receptor would be activated and the PSP would be depressed. Thus GABA could elicit a dual, excitatory and inhibitory action depending on its concentration. In the third possibility, there could exist two subtypes of GABA, receptors on postsynaptic sites responding to GABA and muscimol. One subtype could mediate excitation, responding to lower concentrations of GABA (high-affinity receptor for GABA), and the other could mediate inhibition, responding to greater doses of GABA (low-affinity receptor for GABA). At the lower concentrations of GABA, only high-affinity receptors would be activated and induce excitation. On the other hand, with the application of high amounts of GABA, lowaffinity receptors would be activated, and the PSPs would be depressed as a result. Concerning the excitatory effect of GABA at the lower concentrations, bicuculline instead enhanced the amplitudes of PSPs (Fig. 3). In this case the existence of a new subtype of GABA, receptor could be suggested because this receptor (high-affinity) would be activated by muscimol but not blocked by bicuculline. Concerning the dual effect of GABA, Andersen et al. (1980) and Thalmann et al. (1981) have reported a depolarizing and a hyperpolarizing effect of GABA in hippocampal CA1 neurons. Andersen et al. (1980) reported that iontophoretic application of GABA to the dendritic region depolarized the CA1 neuron, while application to the cell soma hyperpolarized the membrane potential, although it was not determined whether this depolarization actually induced excitation. This result could indicate the presence of two receptive regions on a single neuron for a single transmitter. Kandel and others (Wachtel and Kandel, 1967; Blankenship et al., 1971) reported that acetylcholine had a similar dual effect, excitation and inhibition on a single cell (L7) in the abdominal ganglion of Aplysia. These authors suggested that there are two different receptors for one transmitter, one related to excitation (easily desensitized) and another related to

255

inhibition. Sivilotti and Nistri (1986) have also recently reported that glycine shows a biphasic excitatory and inhibitory effect on neurotransmission in the tectum of the frog. The mechanism of the dual effect of GABA in these experiments has not been fully determined. These novel excitatory and inhibitory effects of GABA in the SC may play important roles in regulating the integrative function of the SC.

Functional aspects of GABA in the SC CAM-sensitive neurons in SC and modification of saccadic eye movements The superior colliculus is well known to be involved in eye movements, particularly saccadic eye movements (Wurtz and Albino, 1980). Cells in the intermediate layer are normally silent, but become active before saccades which are directed contralaterally. The information is sent to neurons in the brainstem reticular formation and is used for creating a motor signal for saccades. It has been shown that the saccade related cells within the SC are under tonic inhibition exerted by cells in the pars reticulata (SNr) of the substantia nigra. Before saccades to visual targets, SNr cells briefly reduce the inhibition, allowing a burst of spikes in SC cells that in turn lead to the initiation of a saccade. Accumulating pharmacological studies support physiological evidence that the nigro-tectal pathway is GABAergic. The concentrations of GABA and GAD are high in the SC (this chapter) and GAD activity is significantly reduced after destruction of the SN (Vincent et al., 1978; Dichiara et al., 1979). Iontophoretic application of GABA readily suppresses the activity of SC cells. The synaptic inhibition induced by SN stimulation can be counteracted by the iontophoretic injection of bicuculline (Chevalier et al., 1981). On the basis of these results, Hikosaka and Wurtz (1985a) injected GABA agonists and antagonists into the monkey's SC to determine the role of GABA in saccade generation. GABA application disrupted saccadic eye movements. Muscimol delayed,

L

-I

L

Fig. 4. Irrepressible saccade jerks induced by the blockade of the nigrocollicular tonic tonic inhibition. In (A) bicuculline was injected into the SC and in (B) muscimol into substantia nigra pars reticulata. The bottom figure below each scheme shows trajectories of saccade jerks during a fixation period after the drug injections. The monkey made irrepressible saccades toward the contralateral visual field. By injections, efferent neurons in the superior colliculus are released from the nigra-induced tonic inhibition, providing the brainstem saccade generator with continuous command signals as expressed by a thickened axon (arrow) of collicular cell in the scheme (data from Hikosaka and Wurtz, 1985a,b).

slowed, or shortened saccades made to visual or remembered targets. Injection of bicuculline facilitated the initiation of saccades (Fig. 4). Injection was followed almost immediately by stereotyped and apparently irrepressible saccades made toward the center of the movement field of SC neurons at the injection site. The eye position shifted toward the side contralateral to the injection, and saccades to the contralateral side increased in frequency. To investigate the involvement of other afferent GABAergic connections to SC or other GABA neurons within the SC, Hikosaka and Wurtz (1985b) modified the neural activity of SNr neurons which receive GABAergic input from the striatum (Okada, 1976b; DiChiara, 1980). Injections o€muscimol into the SN showed the same general effect as bicuculline in the SC (Fig. 4). These results strongly suggest that the SN exerts a tonic inhibition on saccade-related neurons in SC and that the inhibition is mediated

J

256

by GABA. These authors conclude that the basal ganglia contributes to the initiation of movements by a release of the target structure from tonic inhibition, and they suggest that this mechanism must be critical for generating movements that are based on stored or remembered signals that are not currently available to the animal. Involvement of SC in the propagation of seizures Because of the inhibitory action of GABA, the level of GABA helps control the neural activity in the brain. A decrease of GABA in the brain causes convulsions while the GABA agonists and drugs which increase GABA concentration have been used for clinical therapy as anticonvulsants. Concerning transmission at the level of the colliculus, GABA may control the propagation of generalized seizures. Injection of GABA antagonists into the SC and the inferior colliculus resulted in the occurrence of running fits followed by tonic and clonic convulsions (Yamashita and Hirata, 1978; Millan et al., 1986). A decrease of GABA levels in the colliculus correlated well with the appearance of seizure afterdischarge in the slices of inferior colliculus (Yamauchi et al., 1989). Bilateral ablation of the SC abolished the anticonvulsant effects of the intranigral injection of muscimol (Galant and Gale, 1987) while the intracollicular application of bicuculline reduced seizure activity after maximal electroshock (Dean and Gale, 1989). A selective destruction of the SC facilitated the development of kindling and increased afterdischarges and motor seizures (N’gouemo and Rondouin, 1990). Nitsch and Okada (1976) indicated the involvement of SN in the occurrence of generalized seizures, showing a correlation between the decrease of GABA concentration in discrete regions of brain and seizure discharges produced by application of methoxypyridoxine, a vitamin B6 antagonist. Gale and her colleagues found that the nigro-collicular GABAergic pathway is involved in the control of generalized convulsive seizure activity (Gale, 1985). Potentiation of GABAergic transmission within SN by bilateral

microinjections of muscimol or gamma-vinylGABA was found to suppress generalized convulsive seizures in the rat (Gale, 1985; Gonzalez and Hettinger, 1984; Iadarola and Gale, 1982). Bilateral injection of a GABA agonist in SN also suppressed generalized non-convulsive petit ma1 seizures (Depaulis et al., 1988; Depaulis et al., 1989). These reports indicate that the GABAergic nigrocollicular pathway may function as a gating mechanism for generalized seizures. The inhibition of SN efferents has an antiepileptic effect, presumably by disinhibiting the collicular cells which suppress the propagation of seizures. Which neurons in SC are responsible for anticonvulsant effects and which are the target cells of the nigrocollicular projection must be studied further.

LTP formation in SGL and the role of GABA In, 1973, Bliss and Lomo (1973) discovered the phenomenon of long-term potentiation (LTP) in the hippocampus of the rabbit which was maintained for long periods after tetanic stimulation. LTP formation is interpreted to be a substantial increase in synaptic efficacy. The phenomenon has attracted great interest because of the possibility that LTP might underlie some aspect of memory storage. For this reason, research findings on the formation of LTP in the mammalian brain have mainly come from studies of the hippocampus (Teyler, 1987; Collingridge, 1987; Lynch et al., 1990). On the other hand, it has been suggested that LTP might represent a general synaptic plasticity for modifying synapses throughout the brain. If this is so, it would be expected that LTP could be reliably recorded in many parts of the central and peripheral nervous system. Besides the hippocampus, the LTP phenomenon has been observed in several areas of cerebral cortex (Komatsu et al., 1983; Voronin, 1985, Kimura et al., 1989; Artola et al., 19901, the limbic forebrain (Racine et al., 19831, the medial geniculate body (Gerren and Weinberger, 19831, and the deep cerebellar nuclei (Racine et al., 1986). LTP also

257

has been observed in non-mammalian neural tissue such as goldfish tectum (Lewis and Teyler, 1986). However, the properties and mechanism of LTP in tissues other than the hippocampus have not been studied extensively. We have reported LTP formation in the SGL of the SC in in vitro (Okada, 1989; Okada and Miyamoto, 1989; Miyamoto et al., 1990) and in vivo (Shibata et al., 1990) preparations (Fig. 5 and Fig. 6) and shown that LTP formation can be modified by GABAergic interneurons within the SGL. After electrical stimulation of the OL in SC slices, the PSP was recorded in the SGL of the SC as described previously (Fig. 1). Degeneration studies of retinotectal or corticotectal inputs to the SGL of the SC indicated that the PSP evoked in the SGL of SC slices was retinotectal in origin (Miyamoto et al., 1990). Neurotransmission in this pathway may be mediated by glutamate, be-

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20

30 min.

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50

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Fig. 5. The appearance of LTP in SGL of SC slice and the time course of a typical example of the LTP formation. Right panel shows the PSPs elicited in the SGL of the SC slice after the stimulation to OL. (1) indicates the PSP of maximum amplitude with one test stimulus. In (2) the stimulus intensity was adjusted to evoke PSP for the amplitude to be about 1/3 of the maximum amplitude. (3) and (4) show potentiated PSPs 5 and 15 min after the tetanic stimulation (50 Hz,20 sec), respectively. Furthermore ( 5 ) and (6) show more potentiated PSPs 10 and 20 min after the second tetanic stimulation, respectively. Left panel indicates the time course of LTP formation of the slice shown in the right panel. In the figure the adjusted amplitude of PSP in (2) of right panel was taken as 100%. At tet 1, the tetanic stimulation was applied to OL.

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(A)

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20

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40

60

Fig. 6. An example showing the occurrence of LTP in the postsynaptic potential evoked in SGL of the rat in vivo after ablation of the ipsilatearl visual cortex. Before the experiment, the right visual cortical area was aspirated. The postsynaptic field potential was recorded at the surface of the right SC after stimulation of the optic nerve. Stimulus intensity was adjusted to obtain the negative wave at the surface whose amplitude was one-third of the maximum (evoked by the supramaximal stimulation). Twenty minutes after the tetanic stimulation (100 Hz for 10 sec), the amplitude of the negative wave increased to 150% of the original level. The line with closed circles in B shows a typical example of LTP formation. Tetanic stimulation was applied at the arrow. The line with the open circles represents the case in which no tetanic stimulation was applied. In the insert figures at the top, (Al) and (AZ),the potentials just before and 20 min after tetanic stimulation are shown. The amplitude was measured from the peak of the negativity to the baseline. In the bottom figure, the amplitude just before the addition of tetanic stimulation was taken as 100%.

cause the PSP amplitude was reduced or blocked by application of kynurenate or quinoxaline dione (DNQX) to the medium. Furthermore, the concentration of glutamate in the right SGL was significantly reduced by 32% after left optic tract denervation and by 30% after ablation of the right visual cortex, compared with that in the left SGL. LTP in the SGL of SC slices was induced by tetanic stimulation to the OL. The optimal stimulation parameters for inducing LTP were 50 Hz frequency and 20 sec duration (Miyamoto and Okada, 1988). In the granular layer and CA1

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region of hippocampus, activation of NMDA receptors has been reported to be essential for LTP (Collingridge and Bliss, 1987). However, this is not the case for LTP in the SC because NMDA receptor antagonists such as D-APV only mask the appearance of LTP during its application (Miyamoto et al., 1990). LTP formation in the hippocampus has been reported to be mediated by metabolic processes involving protein kinase C (PKC) (Lovinger et al., 1987; Malenka et al., 1987) and this is true for LTP in the SGL (Tomita et al., 1990). In invivo preparations in the rat, we could not induce LTP in the PSP by tetanic stimulation to the optic nerve of the intact animal. However, LTP was elicited by tetanic stimulation either when the ipsilateral visual cortex was removed (Fig. 6) or when picrotoxin, a GABA antagonist, was administered to the animal before tetanic stimulation (Shibata et al., 1990). In the SC slices, the application of GABA to the perfusion medium inhibited LTP formation and application of bicuculline facilitated the induction of LTP (Tomita and Okada, in preparation). These results indicate that GABAergic activity, whether it is extrinsic or intrinsic in the SC, can modulate the induction of LTP in the SGL. Concerning the involvement of GABAergic neurons in modifying LTP formation, application of bicuculline and picrotoxin facilitate the induction of LTP in hippocampal slices (Wigstrom and Gustafasson, 1985). In study of LTP in slice preparations, bicuculline is usually applied to the medium (Kimura et al., 1989). In slices of visual cortex, application of low doses of bicuculline induces long-term depression by tetanic stimulation whereas bicuculline at high doses elicits LTP (Artola et al., 1990). The induction of LTP may thus be influenced by the excitability or the level of membrane potential of postsynaptic neurons which is modulated by GABAergic input. The involvement of extrinsic GABAergic afferents to SC can not be completely excluded as sources of modulation of LTP formation in the SGL. However, the ablation of ipsilateral visual

cortical areas or the application of picrotoxin in animals with an intact ipsilateral visual cortex both facilitate the formation of LTP in vivo preparations. The ipsilateral corticotectal pathway has been reported to exert an inhibitory action on the neural activity evoked by the retinotectal pathway (Mcllwain and Fields, 1979). This inhibition is probably mediated by GABAergic interneurons located in the SGL because the corticotectal pathway is glutamatergic (Fosse and Fonnum, 1986; Sakurai et al., 1990) and many GABAergic interneurons located in the SGL receive corticotectal synapses (Mize, 1988). In the isolated slice preparation of the SC, LTP can be easily induced by tetanic stimulation and the formation of LTP is modified by GABA agonists and antagonists. These results strongly suggest that corticotectal afferents tonically inhibit the induction of LTP that is elicited by tetanic stimulation of the optic nerve, probably by activating GABAergic interneurons within SGL. This ability of neurons to induce LTP in the SC may depend upon the delicate balance between excitatory and inhibitory inputs through the retinotectal, corticotectal, or other extrinsic pathways. GABAergic systems thus may have an important role in maintaining a delicate balance of neural activity within SC. The true mechanism and function of LTP formation in the SC in connection with GABAergic inhibitory processes remains to be investigated in further studies. Summary

Laminer analysis of the distribution of GABA and GAD in the superior colliculus has shown that the distribution pattern of GABA within the SC is smilar in rabbit, cat, and guinea pig. The highest levels of GABA were found in the superficial gray layer (SGL), averaging 37-40 mmol/kg dry weight. The GABA concentrations in the deep layers were each only half that of the levels in the SGL. The concentrations of both GABA and GAD in the upper half of SGL are the same as those in the substantia nigra and medial fore-

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brain bundle which have the highest amounts of GABA in the CNS. Denervation studies of the fibers projecting to SGL suggest that the GABA concentrated in the SGL is intrinsic to the layer. The results obtained from immunohistochemical and electron microscopic studies on the localization of GABA neurons corresponds well with the regional distribution pattern of GABA and GAD reported here. However, pharmacological and electrophysiological studies do not necessarily accord well with the GABA distribution studies because they indicate that there are many GABA sensitive neurons in both the SGL and DGL. To investigate the role of GABA in the SGL, the effect of GABA and its agonists and antagonists on neurotransmission in SGL has been studied in SC slices in a perfusion system. Bath applied GABA (100 p M to 1 mM) enhanced the amplitude of postsynaptic field potentials (PSP) in SGL in a dose-dependent fashion and at concentrations above 1 mM it depressed the PSP in a dose-dependent fashion. A similar response pattern was obtained with muscimol (0.1-10 p M excitation; > 10 pM inhibition). However (-1baclofen only inhibited the PSP. Bicuculline (1 pM) shifted the dose-response inhibitory curve of GABA to the right, while the excitatory effect was enhanced. These results indicate that GABA has an excitatory and inhibitory action on neurotransmission in the SGL. The nigro-tectal GABAergic fibers terminate in the intermediate and deep layers of SC. Inhibition of GABAergic activity in the SC causes irrepressible saccades made toward the center of the movement field while GABA activation delays and slows saccadic eye movements. Thus, GABA in the SC plays an important role in the control of eye movements. The same GABAergic projection is also related to the propagation of generalized sezures. There exist collicular neurons which suppress the propagation of seizures. The activation of these neurons by disinhibition of the tonic action of the GABAergic nigro-tectal input to SC exerts antiepileptic effects. GABA in the SC thus appears to control the gating of

generalized seizures. Long-term potentiation (LTP), which has been extensively studied in the hippocampus, can also be evoked in the SGL of the superior colliculus after tetanic stimulation of the optic nerve. Application of GABA in the medium depresses the formation of LTP in the SGL of SC slices. In in vivo preparations, LTP in the SGL can be induced only when the ipsilateral visual cortex has been removed or when picrotoxin, a GABA antagonist, is administered to the animal before tetanic stimulation. GABA in the SC may be involved in the modification of LTP formation in SGL, probably through intrinsic GABA neurons. In conclusion, GABA is found in high levels in the mammalian superior colliculus and plays an important role in integrating inputs from the cortex, retina, and brainstem. The neural circuits underlying this integration are as yet poorly understood. References Andersen, P., Dingledine, R., Gjestad, L., Langmoen, LA. and Mosfeldt Laursen, A. (1980) Two different responses of hippocampal pyramidal cells to application of gammaaminobutyric acid. J. Physiol., 305: 279-296. Arakawa, T.and Okada, Y. (1987) Dual effect of y-aminobutyric acid (GABA) on neurotransmission in the superior colliculus slices from the guinea pig. Proc. Japun Acad., 63: Ser.B, 389-392. Arakawa, T. and Okada, Y. (1988) Excitatory and inhibitory action of GABA on synaptic transmission in slices of guinea pig superior colliculus. Eur. J. Pharmacol., 158: 217-224. Artola, A,, Brocher, S. and Singer, W. (1990) Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex. Nature, 347: 69-72. Blankenship, J.E., Wachtel, H. and Kandel, E.R. (1971) Ionic mechanisms of excitatory, inhibitory, and dual synaptic actions mediated by an identified interneuron in abdominal ganglion of Aplysia. J. Neurophysiol., 3 4 76-92. Bliss, T.V.P.and Lomo, T.J. (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anesthetized rabbit following stimulation of the perforant path. J. Physiol:, 232: 331-356. Bowery, N.G. and Brown, D.A. (1974) Depolarizing actions of y aminobutyric acid and related compounds on rat superior ganglia in vitro. Br. I. Phamcol., 5 0 205-218.

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