Enhanced response of cortical neurons to thalamic stimuli precedes the appearance of spike and wave discharges in feline generalized penicillin epilepsy

Brain Research, 278 (1983) 207-217 Elsevier

207

Enhanced Response of Cortical Neurons to Thalamic Stimuli Precedes the Appearance of Spike and Wave Discharges in Feline Generalized Penicillin Epilepsy GEORGE KOSTOPOULOS* and MASSIMO AVOLI

Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montrdal, QuL H3A 2B4 (Canada) (Accepted March 1st, 1983)

Key words: cortical neurons - - spike-wave discharges - - penicillin epilepsy

Peristimulus time histograms of extracellularly recorded action potential discharges of cortical neurons in response to single shock and/or repetitive stimulation of 'specific' and 'non-specific' nuclei of the thalamus were studied after i.m. penicillin injection during a period corresponding to that of the development of spike and wave (SW) discharges of feline generalized penicillin epilepsy (FGPE). After i.m. penicillin cortical neurons displayed an enhancement of both the excitatory and 'inhibitory' phases of their responses to single shock stimulation of n. centralis medialis (NCM). This increase was even more pronounced for responses induced by repetitive stimulation of NCM at the frequencies inducing typical recruiting responses. These changes always preceded the appearance of SW discharges. Changes of the responses of cortical neurons to single shock and repetitive stimulation of 'specific' thalamic nuclei after penicillin were weak and inconsistent, although when observed were characterized by an enhancement of both excitatory and 'inhibitory" phases. The latter appeared not to decrease after i.m. penicillin. These data suggest that the appearance of SW discharges of FGPE is closely related to an increased responsiveness of cortical neurons to thalamocortical volleys arising from the so-called 'non-specific' nuclei. This facilitation of the recruiting process is accompanied by an increase of both excitatory and 'inhibitory' phases of the cortical neuronal responses induced by the volleys. INTRODUCTION In the light of recent e x p e r i m e n t a l evidence it has been p r o p o s e d that spike and wave (SW) discharges of feline generalized penicillin epilepsy (FGPE)26 develop from spindles as a consequence of a penicillininduced increase of cortical excitability 12.21-23. Thus in F G P E the 'spike' of the S W complex is thought to represent an enhanced spindle wave, while the 'wave' of SW complex is assumed to reflect inhibition imposed on cortical neurons through the activation of the high threshold cortical inhibitory interneuron 12.21-23, the latter conclusion being in line with earlier findings g a t h e r e d by Pollen in a different experimental model of SW discharges 25. The evidence that cortical neurons after i.m. penicillin respond more vigorously to spindle-inducing thalamocortical volleys is, however, indirect. It is based upon the following observations: surface neg-

*

ative spindles, so-called type II or 'recruiting' spindies, which are thought to reflect EPSPs at apical dendritic locations do not a p p e a r to be associated with a high probability of cortical neuronal firing8,23,31.34. A f t e r penicillin, however, these spindles increase in amplitude and develop positive phases, this change being associated with an increase in neuronal firing probability 23. Thus the spindles assume the features characteristic of type I or ' a u g m e n t i n g ' spindles which are thought to reflect s u m m e d EPSPs at synapses closer to the soma 8,31,34. A s this process progresses further, this leads to the transformation of the spindle waves into the 'spike' of SW complex 22,23. Confirmatory evidence for a penicillin-induced shift of emphasis from m o r e superficial to relatively deeplying thalamocortical synapses 17 has also been obtained by analyzing the laminar surface to depth profiles of spindles and of 'spike' of S W discharges 20 and the changes of the m o r p h o l o g y in recruiting re-

To whom correspondence should be addressed at the Department of Physiology, University of Patra, School of Medicine, Patra, Greece.

0006-8993/83/$03.00 © 1983 Elsevier Science Publishers B.V.

208 sponses (RR) after systemic or widespread cortical application of penicillin 4,17. In the light of these findings it appeared of interest to study whether the responses of cortical neurons located in two different cortical areas (a motor and an associative one) to stimuli applied in 'specific' and "non-specific' nuclei of the thalamus I are changed after i.m. injection of penicillin and to determine how these changes are related to the development of SW discharges of FGPE. The experiments described in this paper were designed to answer these questions. Preliminary data have been reported elsewhere 18. METHOD Acute experiments were carried out on 77 unanesthetized and painlessly immobilized cats. The surgical, anesthetic and analgesic procedures were those described previously 4.22. The pericruciate (PC) and/or the anterior part of the middle suprasylvian gyrus (MSS) were exposed for recording. Bipolar concentric stimulating electrodes were stereotaxically placed in nucleus centralis medialis (NCM), nucleus lateralis posterior (LP), nucleus ventralis lateralis (VL) and the cerebral peduncle (CP) according to the coordinates of the atlas of Jasper and Ajmone-Marsan 15. Stimulation of CP was used for the identification of long axon neurons in the PC. Histological verification of the correct electrode position was carried out in several experiments. E E G and extracellular single unit recordings were performed using the techniques previously described 6,19.23. The presence of a reliable response of a cortical neuron to thalamic stimuli (up to 1 mA, 0.5 ms) was established with peristimulus time histograms (PSTHs) generated on-line by a PDP-11/60 computer. We used both single shock (frequency < 2 Hz, usually 0.2 Hz) and repetitive stimulation (trains of 3-6 stimuli at 5-10 Hz repeated every 5-10 s). After verifying the stability of the response (2-4 PSTHs as controls) 350,000 I. U./kg of penicillin were injected i,m. The study of the evoked responses was then repeated at intervals of 5-10 min while keeping the stimulus parameters constant and observing the E E G changes associated with the development of FGPE.

RESULTS In both cortical areas studied (i.e. MSS and PC) a distinction was made between "specific' (i.e. those evoked by LP or VL, respectively) and 'non-specific' thalamocortical responses (i.e. those evoked by NCM) according to the site of stimulation in the thalamus I and the characteristics of the elicited E E G and unitary cortical responses ~,2~.2~,31.~3.

The effect of penicillin on 'non-specific' (diffuse) thalamocortical responses" Before penicillin single shock stimulation of NCM was without apparent effect on 27 of 45 MSS neurons. When present, the response was excitatory (3 neurons) or more often biphasic (15 neurons), i.e. excitation followed by qnhibition' (Fig. 1A-C, controls). The excitation gradually reached levels 50-100% higher than the background (prestimulus) activity (mean latency 24 ms, mean duration 40 ms) and always preceded the 'inhibitory" period (mean latency 70 ms, mean duration 75 ms). We could not clearly establish different stimulus current thresholds for the two phases of this thalamocortical response; it appeared that any increase in the amount of excitation was accompanied by a corresponding increase in the 'inhibition" of the neuron (not shown). In 17 experiments the same neuron was studied with single shock stimulation of NCM both before and after penicillin during the development of FGPE, An enhancement of the non-specific thalamocortical responses was observed in 9 neurons (53% of the total population studied), while no apparent change was noticeable in the remaining ones (Table I). Both the excitatory and the 'inhibitory" phases were enhanced: the excitatory phase increased by 50--400% as compared to the corresponding response before penicillin, while the 'inhibitory' one was enhanced to the point that firing probability reached zero for 50-100 ms (Fig. 1A-C). A rebound excitatory phase which followed the 'inhibitory' one started to appear after penicillin or was enhanced if present in the prepenicillin PSTHs (Fig. 1A). The increase of these phases started to become evident about 20 rain after penicillin, it continued to increase with time and showed a maximum 1-2 h after penicillin when SW activity usually appeared. Often at a later stage, before or at the time of the

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Fig. 1. Increase of the response of MSS neurons to single stimuli in NCM (filled circles) in successive PSTHs before (control) and at the times indicated (numbers on the left) after i.m. penicillin. In this and the following figures numbers in ordinate represent the action potentials/bin. A: before penicillin NCM stimulation (0.2 Hz; 0.5 mA; 0.5 ms) evokes initially a moderate excitation followed by a questionable weak period of 'inhibition' and a long-lasting rebound excitation. Already 8 min after penicillin all 3 phases of this response are increased. The initial excitation has more than doubled in strength and duration, the latter being curtailed in subsequent PSTHs by the increased strength of the 'inhibitory' phase. Comparison of all subsequent PSTHs reveals a correlation between the strength of the excitatory phase to the duration of the 'inhibitory' phase. Note that the background activity, expressed as the average number of action potentials/bin (bin width = 6 ms) in the prestimulus period of 0-600 ms (numbers above prestimulus part of PSTHs), only slightly increases during the transition while a decrease is observed at +73. The excitatory phase (7 bins, i.e. 42 ms, following the stimulus) changes as follows: control = 68% increase compared to background firing, +8' = 158%, +20' = 187%, +47' = 168%, +73' = 576%. The second excitatory phase also increases and gradually evolves into an oscillation between excitation and 'inhibition'. This oscillation finally corresponds to the SW rhythm in the EEG evident at that time (bottom sample), 150 repetitions in each PSTH. B: both the initial (30-90 ms) and the much longer duration rebound excitation induced by NCM stimulation (0.1 Hz; 1.0 mA; 0.5 ms) is enhanced while a strong 'inhibition' develops after the initial excitatory phase. The periodic increases in activity during the rebound excitation at 55' correspond to the 'spike' component of SW discharges triggered by the NCM stimulus at that time. To the right of the initial excitatory response (100 ms following the stimulus) the average number of action potentials/bin (bin width = 2 ms) is given for the bracketed period. Eighty repetitions for each PSTH except the one at +22' where there are only 40. C: in contrast to the usual trend this particular MSS neuron, similarly to that in A, shows a gradually decreasing background activity after penicillin (see prestimulus period). In spite of this the excitatory phase of the NCM induced response (0.2 Hz; 1.0 mA; 0.5 ms) is increased (bin width = 1 ms, 200 repetitions in all PSTHs).

210 TABLE I Changes in 'non-specific' and 'specific' thalamocortical responses induced by penicillin Numbers refer to number of neurons tested (total) and to their responsiveness to stimulation (unaffected vs increased responsiveness) Stimulation and

Single shock stimulation (<~2 Hz)

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5 (83%) 9 (53%)

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5 (83%) 12 (86%)

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I (10%) 2 (29%)

10 4

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stances in which the overall firing gradually decreased with time (Fig. 1C). Unitary responses of MSS neurons to repetitive stimulation of NCM when studied in PSTHs (46 neurons) before penicillin displayed the features characteristic for R R 28.31,33. Thus the first stimulus was marginally, if at all effective, but there was a gradual in-

first SW discharges, an even stronger increase of the rebound excitation was observed which was eventually terminated by a second 'inhibitory' period. This ultimately led to an oscillatory pattern in the PSTH characterized by oscillations between maximum and m i n i m u m firing probabilities lasting for 1-2 s in obvious correlation with the 'spike' and the 'wave' components of the SW complexes (Fig. 1A, +73; B, +55). At this time SWs occurred spontaneously and were almost consistently evoked by NCM single shock stimulation4.22 (Fig. 1A). As reported previously, the overall firing of the neurons increased in many cases after penicillin23.

crease of both the excitatory and the subsequent 'inhibitory' phases of the biphasic response from the 2nd to the 3rd, 4th, 5th or 6th stimulus in a train of stimuli (Fig. 2, controls). After penicillin PSTHs demonstrated an increase

However, this was not a necessary condition for the

i.e. the response to the 2nd stimulus was more intense than the response to the 2rid stimulus in control conditions (Fig. 2A, B), The same was true for the 3rd, and the subsequent stimuli. This p h e n o m e n o n

of the homologous responses within a stimulus train,

effect exerted by penicillin on the stimulus-induced activity, since the e n h a n c e m e n t of the excitatory and 'inhibitory' phases was even more evident in in-

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211 was observed in 12 of 14 experiments (Table I), including cases in which the enhancement of the response to single shock NCM stimulation could not be demonstrated. The enhancement of R R began to appear about 20 min after penicillin injection, i.e. some time before the appearance of SW discharges. However, the maximum increase was usually reached at the time when well developed SW bursts appeared, namely within the first 2 h after penicillin. As shown in Fig. 2 these changes were gradual and involved both the excitatory and the 'inhibitory' phases. Furthermore, the maximum response within a given train of stimuli occurred earlier after penicillin than in the control condition (e.g. 3rd stimulus at +185 versus 6th stimulus before penicillin in Fig. 2B). In some cases the enhancement of the 'inhibitory' phase manifested itself also in an apparent increase of the latency of the excitatory phase (e.g. compare in Fig. 2A the latency of the excitatory phase of the 4th response at +68' with that of the excitatory phase of the 1st response at +68' or of the 4th one in control). Also, after penicillin there was a reduction in the duration of the excitatory phase in spite of its increased intensity, probably because of the enhancement of 'inhibition' which followed the excitatory phase subsequent to the preceding response (Fig. 2). Similar results were observed before penicillin with single and repetitive NCM stimulation in 28 PC neurons, 13 of which were antidromically activated from CP (parameters as those used for MSS neurons). Although the characteristics of the biphasic response to single shock stimulation of NCM were very similar, a smaller number of PC neurons responded to NCM as compared to MSS ones. In 6 experiments (4 of these units were antidromically activated from CP) we were able to follow the response of the same PC neuron to NCM stimulation before and after penicillin. An increase of both the excitatory and 'inhibitory' phases of the response to single and to repetitive NCM stimulation was observed in 5 of these neurons, two of which had been unresponsive to NCM stimulation before penicillin (Fig. 3), Changes in E E G RR after penicillin 4;17 were related to changes in unitary activity (Fig. 3A). Thus an increased firing of the CP neuron corresponded in time and developed in parallel to a surface positive, deep negative phase of the E E G R R (compare the response to the

5th stimulus of the train in the last 3 traces of the control and the corresponding traces at 64' after penicillin). It is of interest that in two PC neurons a potent 'inhibitory' period preceding the excitatory one appeared in response to NCM stimulation after penicillin (Fig. 3C, first response at +36).

The effect of penicillin on the 'specific' thalamocortical response The responses of MSS neurons to LP single shock stimulations were studied in 25 neurons, of which 21 were excited at a short latency 35 (13 at 2-5 ms and 8 at 8-15 ms). Often two peaks corresponding to these two latency ranges of time were observed in the PSTH (Fig. 4B and C, controls). Four neurons in MSS were antidromically activated from Lp6,3s. In all the neurons orthodromically activated a strong 'inhibition' (duration 80-150 ms) followed the excitation. In 14 of these 21 neurons a late rebound excitation followed the 'inhibitory' period and lasted for up to 500 ms (Fig. 4A and B, controls). With repetitive stimulation we observed only a relatively small increase of the response, which affected mainly the excitatory phase characterized by 8-15 ms latency (13 neurons). At times the appearance of a new peak of excitation with the 2nd or 3rd repetition of the stimulus was seen (Fig. 4C). In some cases in which the 'inhibition' had not already reached zero firing probability with the first stimulus the 'inhibition' was also enhanced. The changes induced by penicillin on the responses of MSS neurons to single shock stimulation of LP were weak and inconsistent (Fig. 4A) when compared with those observed with NCM stimulation. Thus in only 2 of 7 MSS neurons studied before and after penicillin was there some increase of the excitatory phase of the response to single shock LP stimulation. This increase affected mainly the excitatory response occurring at 8-15 ms latency and in one case a period of secondary excitation appeared (Fig. 4B). The 'inhibitory' phase was enhanced only in 1 case and the rebound excitation increased after penicillin in 2 of the 5 neurons in which it was present under control condition (Fig. 4B). When the response of MSS neurons to repetitive stimulation of LP was studied before and after penicillin (4 experiments), an enhancement of the responses was observed in only one MSS neuron (Fig.

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Fig. 4. PSTHs of the response (before and at the indicated times after penicillin) of 3 MSS neurons to LP stimulation (triangles). A: PSTHs show changes which occur mainly at the time of appearance of SW discharges (+65 min) and thereafter; 100 repetitions in each PSTH. Stimulus parameters 1.2 mA, 0.1 ms. Bin width = 4 ms. B: mainly the 2nd peak of the short latency excitatory response (star) is increased after penicillin. At + 70 a period of secondary excitation (arrow) as well as a late rebound excitation following the unchanged period of decreased firing probability appear. 180 repetitions in each PSTH. Stimulus parameters: 1 mA, 0.2 ms. Bin width = 1 ms. C: one of the two cases where penicillin induced an increase in the response of an MSS neuron to repetitive (9 Hz) stimulation in LP (0.2 mA, 0.1 ms). Bin width = 1 ms; 200 repetitions.

4C). This e n h a n c e m e n t p r e c e d e d the a p p e a r a n c e of S W activity,

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fective in triggering S W discharges. This is e v i d e n t in

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Fig. 4 A w h e r e the P S T H c o m p u t e d after + 6 5 m i n be-

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every 50 ms). An epicortical electrode (e.co.) monitors the EEG in the same area (PC) while 3 other epicortical electrodes record the EEG from the anterior (A) and posterior (P) part of MSS and the contralateral lateral gyrus (Lat). Rt, right; Lt, left. The same calibration applies to the 4 samples which were taken respectively before and at the indicated times after penicillin. Spontaneous SW discharges started at +86'. At + 130' there were clonic electrographic seizure discharges which were restricted to the right hemisphere. They were followed by a postictal depression of the EEG and unit activity on that side. The last group of traces (+ 133) was recorded during partial recovery from this depression. B. PSTHs from the study of the same neuron as in A. The numbers below the brackets in the control sample indicate action potentials/bin for the following 3 periods indicated by the numbered brackets: 1, background activity 400 ms before the stimulus; 2, first response (excitatory phase) to the train of stimuli at 24--72 ms from the first stimulus; and 3, the period of 800 ms which coincides with the whole stimulation period. Bin width = 4 ms. Fifty repetitions in each PSTH. Stimulus train frequency 8 Hz, 0.2 ms. C: another CP cell not responding to NCM stimulation before penicillin. A strong biphasic response to the train of 3 NCM stimuli (5 Hz, 0.1 mA, 0.3 ms) occurs at +36'. In this last PSTH the first excitatory response is absent, while the next one is the strongest. Bin width = 4 ms.

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Fig. 5. Comparison of the response of 3 CP neurons to single VL stimulation (filled triangles) before and at the indicated times after penicillin. A: same cell as in Fig. 3 A and B. Small and inconsistent increase of the initial excitatory response with the only exception of PSTH at + 113 (compare activity calculated for period 1 to that of period 2 which spans 5-15 ms followingthe stimulus). The 'inhibitory' phase increases progressively after penicillin. Stimulation at 2 Hz, 0.2 mA, 0,5 ms; 250 in each PSTH: bin width = 1 ms. B: this neuron displayed an antidromic (not detectable in PSTH) as well as a short latency orthodromic excitation upon single shock stimulation in VL (0.5 mA, 0.1 ms). The latter appears to steadily decrease after penicillin in spite of a gradual increase of the rebound excitation which is almost doubled by +97 rain after penicillin. No evident change of the "inhibitory' period: 200 repetitions; bin width = 1 ms. C: in this CP neuron the prestimulus (PS) activity is increased initially after penicillin and diminishes afterwards. The response to VL stimulation (0.8 mA; 0.5 ms) consists of an initial excitation (E) lasting from 5-15 ms, a long 'inhibitory'period and rebound excitation (RE). Both excitatory phases increase shortly after penicillin and continue to do so even when background activity becomes very low. They are both enhanced by more than 60% at +90' after penicillin. There was no change in "inhibition', 200 repetitions; bin width = lms,

After penicillin, the response pattern of most PC neurons was not changed and neither did the quantitative aspects of the responses. Thus only 1 of 10 PC neurons tested before and after penicillin with single shock stimulation applied to VL displayed a clear and progressive increase of the short latency excitatory response (Fig. 5C). In one case the 'inhibitory' period was increased (Fig. 5A) and in another there was only an increase in r e b o u n d excitation (Fig. 5B). A R induced by repetitive VL stimulation when studied after i.m. penicillin up to the appearance of generalized SW discharges generally showed no significant changes. DISCUSSION This study indicates that the development of SW bursts of F G P E is preceded and accompanied by a

clear increase of the so-called "non-specific' (diffuse) thalamocortical responses s.28,314s. Thus, after penicillin, both the excitatory and the "inhibitory' phases associated with single-shock or repetitive NCM stimulation increased progressively with consequent changes of the PSTH pattern which appeared to assume some of the features typical of A R ~,2s,31.-~3 (compare PSTHs control and + 185 of Fig. 2B with PSTH control in Fig. 4C). The e n h a n c e m e n t of the 'non-specific' (diffuse) thalamocortical responses started to appear about 20 min after the i.m. injection of penicillin, i.e. a considerable time before the appearance of SW discharges, though this increase reached its maximum only when SW activity had fully developed. In contrast, cortical responses to single or repetitive stimulation of the 'specific' thalamic nuclei did not undergo, during SW development, the same dramatic changes observed with 'non-specific' (dif-

215 fuse) thalamocortical responses. Thus the enhancing effect of penicillin upon the responses of MSS or PC neurons to LP or VL stimulation respectively was weak or inconsistent as compared to that observed for the response of the same neurons to NCM stimulation. These observations, which reemphasize the role of 'non-specific', diffuse thalamocortical projections in the pathogenesis of generalized epilepsies associated with SW rhythms 12,16,21 give further support to the concept of a common physiological mechanism shared by spindles and RR on one side and SW discharges of FGPE on the other~,12,20-23. It has been shown that during the development of SW discharges of FGPE both spindle 22 and recruiting waves 4,17 acquire surface positive phases and increase in amplitude. The present study shows that these E E G changes are associated with an increase in the responsiveness of cortical neurons to thalamic stimuli, mainly to those applied to NCM as single shocks or repetitively. Thus, in agreement with a previous study on the microphysiological features of the transition from spindles to the SW discharge of FGPE 22,23, these results demonstrate that the appearance of SW activity is associated with an increase of both excitatory and 'inhibitory' phases of cortical neuronal responses evoked by thalamocortical volleys. The increase in amplitude of RR after penicillin4,~7 has been interpreted as increase of the EPSPs evoked by thalamocortical inputs on apical dendrites 23. Especially the amplitude increase of the positive phases of RR was suggested to represent 17 a shift of emphasis from EPSPs generated on superficial parts of apical dendrites (negative phases, i.e. superficial responses of Sasaki et al. 31) to EPSPs, generated closer to the soma of cortical neurons (positive phases, i.e. deep responses of Sasaki et al.3~). Whatever the mechanisms of this shift (different possibilities have been discussed elsewhere~7), the present study which shows increased firing of cortical neurons in response to thalamic stimuli, supports the above interpretation, since depolarization of dendritic parts located closer to the soma are considered to be more effective in eliciting action potentials 30. The less consistent and often negative results obtained when studying the cortical responses to stimuli delivered to 'specific' thalamic nuclei after i.m. penicillin does not necessarily imply that 'specific' thala-

mocortical inputs play a minor role in the physiopathogenesis of FGPE, since it has been shown that thalamic neurons in LP are prominently involved in SW discharges 5. On the contrary these findings might be explained by the fact that 'specific' thalamocortical projections are physiologically characterized by a more effective synaptic transfer at the cortical level than is the case for 'non-specific' thalamocortical projections 8. Thus penicillin, at the concentration at which it is present in the cortex in FGPE 29, might be unable to further increase an already highly effective response of cortical neurons to 'specific' thalamocortical volleys, especially those artificially induced by electrical stimuli, while enhancing the cortical responses to thalamocortical inputs characterized by a synaptic transfer which in the normal, non-penicillinized state is weak and relatively ineffectives. We have shown that after penicillin any enhancement of the excitatory phase of the cortical response to NCM stimulation is accompanied by an increase in the strength and duration of the associated period of decreased firing probability (i.e. the 'inhibitory' phase). Furthermore, the period of decreased firing probability evoked by stimuli delivered to the 'specific' thalamic nuclei did not decrease after i.m. penicillin up to and including the stage of SW discharges. Because of the extracellular recordings used in the present experiments, we cannot unequivocally conclude that the periods of decreased firing probability do in fact reflect post-synaptic inhibition. Thus it has been recently shown in both hippocampus 14and neocortex7 that the hyperpolarization following a burst of action potentials reflects a calcium dependent increase in potassium conductance. However, Purpura and Shofer27 have shown that the hyperpolarizing potentials associated with both RR and AR are generated by ionic mechanisms similar to those of IPSP which suggests that the periods of decreased firing probability induced by thalamic stimulation observed in this study most likely represent manifestations of true post-synaptic inhibition. The enhancement or preservation of thalamic induced periods of decreased firing probability after i.m. penicillin is difficult to reconcile with recent evidence indicating that penicillin exerts a potent anti-inhibitory action which may explain its effects including its epileptogenic properties 2,3.9,11,32,37. Nevertheless the lack of any demonstrable effect of penicillin on what most likely

216 r e p r e s e n t s instances of post-synaptic inhibition finds

ACKNOWLEDGEMENTS

support in r e c e n t e x p e r i m e n t s which h a v e s h o w n that cortical r e c u r r e n t inhibition r e m a i n s intact in F G P E

W e t h a n k Dr. P. G l o o r for c o n s t r u c t i v e criticism,

up to and including the t i m e of S W discharge 19 as well

Mrs. S. Schiller and T. de la Fosse for technical assis-

as that after systemic i n j e c t i o n of a m o u n t s of penicil-

tance and Miss G. R o b i l l a r d for secretarial assis-

lin similar to those used in this study, an identified

tance. This w o r k was s u p p o r t e d by the M e d i c a l R e -

monosynaptic,

search C o u n c i l of C a n a d a ( M R C G r a n t M A - 7 7 0 3 to

probably

GABA-ergic

pathway

in

D e i t e r s ' nucleus r e m a i n s functionally u n i m p a i r e d 10.

G.K.).

G . K . was an M R C

F u r t h e r m o r e , in the 'in v i t r o ' h i p p o c a m p a l slice a re-

M R C Fellow.

Scholar and M . A . an

sidual IPSP has b e e n o b s e r v e d during e p i l e p t i f o r m e v e n t s i n d u c e d by bath application of penicillin J3. Intracellular r e c o r d i n g s are, h o w e v e r , r e q u i r e d to conclusively settle this question.

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7

8

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