Cerebellar neuronal activity correlates with spike and wave EEG patterns in the rat

Epilepsy Research, 16 (1993) 1-9 0920-121 l/93/%06.00 0 1993 Elsevier Science Publishers B.V. All rights reserved

EPIRES 00595

Cerebellar neuronal activity correlates with spike and wave EEG patterns in the rat

Adam Kandel, Gyijrgy Buz&ki*

Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey,

197 University Avenue, Newark, NJ 07102. USA

(Received 28 January 1993; revision received 10 April 1993; accepted 26 April 1993)

Abstract

In this study we investigated the involvement of the cerebellum in high voltage spike-and-wave spindles, a rodent model of petit mal epilepsy. High voltage spindles, recorded epidurally from the sensorimotor neocortex, were correlated with single or multiple unit activity in the cerebellar cortex and deep cerebellar nuclei. The majority of neurons or neuronal groups in the cerebellum (77.9%) fired rhythmically and phase-locked with the high voltage spindles, either during the spike (43.2%; n =41) or during the wave (34.7%; n = 33) component of the high voltage spindle. Tremor of the head and neck musculature, recorded with an accelero-meter, occurred during the high vohage spindle in approximately half of the rats. When present, rhythmic movement occurred predominantly during the wave phase of the high voltage spindle. The remaining half of the rats did not show tremor during high voltage spindles but, nevertheless, had cerebellar units that burst during the spike or wave phase of the high voltage spindle. These latter results demonstrate that phase-locked bursting of cerebellar units during high voltage spindle is independent of rhythmic movement. The findings suggest that rhythmic output from the cerebellum may contribute to the maintenance of generalized petit ma1 seizures.

Key words: Petit ma1 epilepsy; Cerebellum; Unit activity; (Rat)

1. Introduction

High voltage spike-and-wave spindles (HVS), which appear during immobility and sleep in various strains of rodents, represent an animal model for the spike-and-wave patterns found in children with petit ma1 epilepsy [22,30,31]. These cortical events are thought to be initiated in the thalamus [4,27]. Rhythmic thalamic neuronal network bursts precede cortical HVS patterns and the ventral anterior and the ventral lateral (VA/VL) thalamic nuclei have been implicated as the regions where

*Correspon~ng author. Tel.: (201) 648-1080 ext. 3131; Fax: (201) 648-1588.

these oscillations are initiated in man and in rodent models for petit ma1 epilepsy [4,5,14,27].

A major input to the ventrobasal complex (VA/ VL nuclei) of the thalamus originates from the cerebellum [16]. Most of the thalamofugal efferents from the cerebellum project directly onto thalamocortical cells via the superior cerebellar peduncle [1,33]. These efferents originate solely from the deep cerebellar nuclei: the dentate, interpositus and fastigial nuclei. The dentate and interpositus nuclei form topographical connections with the VAjVL thalamic nuclei while the fastigial nucleus is thought to have connections predominantly with limbic structures (amygdala and hippocampus) [1,12,15].

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Given the intimate relationship between the cerebellar output and the ventrobasal region of the thalamus, we sought to investigate the possible involvement of cerebellar neuronal activity in HVS. This was accomplished by recording extracellularly from isolated neurons in the cerebellar cortex and deep cerebellar nuclei before and during HVS. Part of these findings have been reported in abstract form [17].

2. Ex~ri~ent~ procedures

2. I. Surgery

Twenty three male and female rats, approximately 6 months of age (200400 g), were used in this study. Fifteen of them were of the WAG/Rij strain from Dr. Gilles van Luijtelaar’s colony (University of Nijmegen, The Netherlands) as well as from Harlan Sprague-Dawley of The Nether- lands. Another eight rats were the Fz descendants of the Brown-Norway (BN) and Fischer 344 (F344) inbred strains. This latter group was cho- sen because HVS is often associated with tremor of the vibrissae and head in these rats [28]. The animals were housed in individual cages, given ad libitum food and water and maintained on a 12: 12 1ight:dark cycle. They were anesthetized with a mixture of ketamine (25 mg/ml), xylazine (1.3 mg/ ml) and acepromazine (0.24 mg/ml) at a dosage of 4 ml/kg of weight. Following anesthesia animals were placed in a Kopf stereotaxic instrument. For recording cortical field potentials (EEG) four stainless steel epidural electrodes were placed bilat- erally in the skull (AP = 0.0 mm; L = f4.5 mm; AP = 2.5; L = +2.5 mm; relative to bregma). An approximately 3 mm diameter piece of the skull over the cerebellum was excised with the center of the hole at AP = 11.5 mm and L = 0.5 mm (relative to bregma). This area is above the largest extent of the deep cerebellar nuclei [23]. A plastic microelectrode drive holder was placed above the hole and fixed to the skull with dental acrylic. Stainless steel screw electrodes just anterior and lateral to the microdrive holder served as ground and indifferent electrodes, respectively.

2.2. Physiological testing

At least 3 days after surgery animals were placed

in clear plastic testing chambers where recording sessions took place. A movable microelectrode drive for recording unit activity was placed in the drive holder. Microelectrodes (l-3 MQ tungsten wire) were inserted eccentrically in the microelectrode drive, which enabled us to record from multiple tracks from within the same opening. Unit activity and neocortical EEG was amplified and fil- tered (Grass model 12). The filters for unit activity were set between 500 Hz and 10 kHz and for the EEG between 1 Hz and 1 kHz. Tremor and movement were recorded with an electrothermomechanical film (ETMF) accelero-meter (supplied from the University of Kuopio, Finland). All animals were able to move freely at all times. Physiological data were sampled at 10 kHz and recorded on a high capacity optical disk. Once a cell or a group of cells was well isolated, with better than 3:l signal/background ratio, recording was initiated. In these studies no effort was made to positively iden- tify the different cerebellar cell types. The relationship between unit firing and HVS was assessed by computing the cross-correlation between these two events using the peak of the spike component of HVS as a reference event. Once testing was com- pleted the animals were perfused with the microelectrode still in the cerebellum. Perfusion was made transcardially with physiological saline fol- lowed by 4% paraformaldehyde. Brains were re- moved and postfixed in paraformaldehyde and were sectioned at 40 mm on a freezing microtome and stained with cresyl violet to verify electrode placement.

3. Results

3.1. Relationship between cerebellar unit firing and

neocor tical H VS

A total of 95 units (multi or single) from the cerebellar cortex and deep cerebellar nuclei were isolated and recorded during HVS. Typical examples are illustrated in Fig. 1. With the exception of putative Purkinje cells, it was not possible to iden- tify the various cell types in the cerebellum. Puta- tive Purkinje cells could be positively identified by the spontaneous occurrence of complex spiking patterns (Fig. 1E) [9]. Interestingly, neurons with complex spikes were rare (less than 10%) either

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A ii-v-v-

Fig. 1. Relationships between cerebellar unit activity, high voltage spindles (HVS) and movement. Examples of single sweeps from

cx

cbl

mov

cbl

mov

cx

cbl

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various recording sessions. Upper traces: HVS recorded from the sensorimotor cortex (cx). Middle traces: single and multiple units from the cerebellum (cbl). Lower traces: movement displacements (mov) measured from the ETMF-accelerometer. Calibrations: 0.5 mV (EEG) and SO ms (units). (A, B) Units from the cerebellar cortex that fired during the wave component of HVS. (C) Units that fired tonically before HVS and with rhyihmic bursts during HVS. (D) Units tiring during the spike component of HVS from the deep nuclei. (E) Putative Purkinje cell; note complex spike bursts during the spike component of HVS. (F) Units from the deep nuclei exhibiting no

altered tiring pattern during HVS.

a. superficial b. superficial c. deep

EEG

i movement i

L -150 -50 50 150ms -150 -50 50 150ms -150 -50 50 150ms -150 -50 50 150ms

d. deep

____ ._ -. __-

Fig. 2. Comparison of unit tiring and movement during HVS from superficial (cerebellar cortex) and deep (deep cerebellar nuclei)

recording sites in the cerebellum. EEG = averages of HVS epochs (n = 216): units = cross-correlo~ams of HVS (spike component)

and unit tiring; movement = cross-correlograms of HVS and movement. (a) Unit activity from superficial layers firing just before the

spike component of HVS with concomitant rhythmic movement and (b) with no movement during HVS. (c) Unit activity from deep

layers tiring during the spike component of HVS with concomitant rhythmic movement and (d) with no rhythmic movement during the

HVS.

because we recorded from mostly non-Purkinje cells or because Purkinje cells only occasionally emitted complex spike burst during HVS. Never- theless, putative Purkinje cells discharged in conjunction with the spike component of HVS in both WAG and F344/BN rats. The identity of other units could not be independently revealed. They were classified according to their relationship to the spike or the wave component of HVS.

The phase-locked relationship between unit firing and HVS was arbitrarily judged reliable when the peak-to-trough ratio exceeded 2:1, because previous studies have shown that such ratios reflect statistically reliable modulation of the histogram. Seventy four of the 95 recorded units (77.9%) showed a reliable correlation with either the spike (n=41, 43.2%), or the wave (n=33, 34.7%) component of HVS (Fig. 2). These distributions were similar in WAG (spike: 32, wave: 26) and F344/ BN (spike: 9, wave: 7) animals. In some rats (n = 5) all isolated units correlated exclusively with either the spike or the wave component of HVS in a given recording tract. In these rats, histology revealed that the electrode penetrated through iden- tical layers (e.g., Fig. 4C, D), suggesting that we

were recording from the same class of cells. How- ever, in the majority of rats of both strains subse- quently recorded units correlated either with the spike or the wave component of HVS. In one case, two separable units were simultaneously recorded; one of them exhibited a reliable correlation with the spike component and the other with the wave component of HVS. It is important to emphasize that a given relationship of the unit with HVS was consistent, and we have never observed that units with a spike or wave preference would change over time. These findings suggest that the correlation of unit firing with various as- pects of HVS is independent of the recording con- ditions or the strain of rats but most likely reflects that the various subclasses of cerebellar neurons have different phase relations to HVS.

Although not quantified systematicaily, we often observed a direct correlation between the amplitude of the neocortically derived HVS and multiple unit bursts (e.g., Figs. lA,D,E). Larger spike components were accompanied by tighter multiple unit activity, Furthermore, putative Purkinje cells fired complex bursts almost exclusively in conjunction with large amplitude spike components (Fig. 1 E).

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Spike Wave Other

Fig. 3. Scatter plot of unit activity as a function of phase of

HVS: spike or wave component. Ordinate: depth from the dor-

sal surface of the cerebellar cortex. Spike = unit(s) that signifi-

cantly fired during the spike component of HVS; wave =

unit(s) that significantly fired during the wave component of

HVS; other = units that failed to show phase-locking to HVS.

Units recorded from 0 to 2.5 mm correspond approximately to

the cerebellar cortex and units from 4.0 to 5.5 correspond to the

deep cerebellar nuclei. The area without units (2.54.0) corre-

sponds to white matter [23].

Units that correlated with either the spike or wave component did not appear to cluster in any particular region of the cerebellar cortex or the deep cerebellar nuclei (Fig. 3.). Reconstruction of the sites of recorded units from all animals revealed two major areas of cellular activity (Fig. 3). The upper region (O-2.5 mm) roughly corresponds to units that were recorded from the cerebellar cortex while the ventral region (45.5 mm) corresponds to units that were recorded from the deep cerebellar nuclei [23].

Electrode placements were verified by cresyl violet staining (Fig. 4). Again, this figure supports the observation that all regions that we recorded from

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contain neurons which correlate with either the spike or the wave component of HVS. Units with no particular relationship with HVS were inter- spersed among these neurons.

3.2. Phase-locking of tremor, HVS and cerebellar activity

Visible rhythmic movements of the vibrissae, head and trunk (tremor) were rarely present in rats of the WAG strain but occurred frequently in the F2 descendants of the Brown-Norway and Fischer 344 strains [28]. HVS-associated tremor was recorded as a change of linear velocity by the ETMF-accelerator device. During analysis the analog signal was rectified. Movement was de- fined by a threshold value set above the irregular deflections recorded during immobility epochs without HVS. The digital output pulses of the movement-detector program were cross-correlated with HVS.

Tremor was present and correlated with HVS in 49 cases (59.7%). Of these, tremor movements occurred during the wave component of HVS (n = 43; 87.7%). In the remaining 46 cases (40.3%) movements of the head and neck musculature were either not present or occurred in an irregular man- ner. More frequently, movement, when present, occurred shortly after the onset of HVS and disap- peared during the latter part of the HVS epoch. These irregular, transient movements did not correlate with any phase of HVS (Fig. 2b,d). These findings therefore provide evidence that peripher- ally observable tremor was not a prerequisite for the HVS-associated rhythmic discharge of cerebellar neurons.

4. Discussion

All rats used in this study contained cerebellar units that displayed rhythmic bursting patterns that were phase-locked to either the spike or the wave component of HVS. Some animals with HVS-associated rhythmic tiring of cerebellar neurons also exhibited rhythmic movements (tremor). However, in several rats HVS was not accompanied by tremor of the vibrissae or the head/neck muscles, although cerebellar units were phase- locked to either the spike or wave component of

Fig. 4. Examples of parasaggital sections containing electrode tracks. Left: anterior, right: posterior, top: dorsal and bottom: ventrat. (A, C) Two different electrode tracks (white arrows) at 10 x . (B, D) Higher magnifications of A and C (25 x ). In tracks A and B the electrode penetrated through successive layers of the foiium, whereas in tracks C and D most neurons were recorded from the same

anatomical layer.

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HVS. These findings suggest that neuronal patterns in the cerebellum may play a role in the maintenance of neocortical spike-and-wave activity in petit ma1 epilepsy.

During HVS neurons from a variety of structures are entrained into rhythmic network activity, including all parts of the neocortex, thalamus, cau- date nucleus, entopeduncular nucleus, basal fore- brain and the locus coeruleus [2,4]. A current view of the generation of neocortically recorded spike- and-wave patterns is that the rhythmic oscillation emerges from the thalamus as a result of the interplay between the intrinsic properties of individual neurons and the thalamocortical network 16,271. The initiation zone of the emergent thalamic oscillation, the ventrobasal thalamic region (VA/VL nuclei), is the main target of cerebellar efferents [l]. Based on the anatomical circuitry alone, one can postulate that rhythmic output from the cerebellum should have an important role in the maintenance and/or frequency modification of thalamic oscillations underlying HVS.

Rhythmic inputs to the cerebellum during HVS may be conveyed by any of the several cerebellofu- gal systems. The two main sources of cerebellar afferents are the climbing fibers, which ascend from the inferior olive, and the mossy fibers origi- nating from the pontine nuclei [9,21]. The cerebral cortex projects indirectly to the cerebellum via the pontine nuclei through the corticopontocerebellar pathway. Importantly, these projections originate from cortical areas 4 and 6, the targets of the ventrobasal thalamus [ 161. The inferior olive receives afferents from large areas of the cerebral cortex and it sends efferents as climbing fibers to the molecular layer of the cerebellar cortex and to the deep cerebellar nuclei [29]. If the cerebellum is in fact synchronized from the cerebral cortex during epilepsy the climbing and mossy/parallel fiber systems would be the most likely candidates by nature of their extensive connections throughout the cerebellar cortex. The exclusive or predominant role of the olivocerebellar system is reduced by our observation that putative Purkinje cells rarely displayed rhythmic complex spike patterns during HVS. Sti- mulation of the climbing fibers invariably induces complex spikes in Purkinje cells [Zl].

Some of the animals in this study displayed HVS-

associated tremor of the vibrissae and head/neck muscles. The objection that rhythmic cerebellar activity is caused solely by peripheral reafferentation can be, however, rejected on several grounds. First, rhythmic bursting units in the cerebellum were equally found in rats with and without tremor. Second, careful inspection of the original records in animals with tremor did not reveal a reliable relationship between the amplitude of tremor and multiple unit activity. Third, in cats with a convulsive form of epilepsy cerebellar activity failed to reveal any correspondence to clonic seizures [lo]. In fact, a major puzzle of petit ma1 epilepsy is the remarkable lack of peripheral muscular activity in spite of the synchronous bursting of neurons in the motor cortex and other motor structures 161.

The modulatory role of the cerebellum in convulsive forms of epilepsies has been implicated by previous research [3,8,10,32]. Electrical stimulation of the cerebellar cortex as well as the superior cerebellar peduncle has been shown to inhibit ongoing seizures and lesions of the cerebellar cortex have increased the severity of seizure activity in rodent models of generalized epilepsy [7,32]. In humans, the cerebellum of some epileptic patients has shown pathological alterations, primarily of the Purkinje cell layer [3,X]. Similar changes have also been seen in animal models for non-convulsive as well as convulsive generalized epilepsies [l&24,25].

~europathological changes have also been reported in mutant mouse models of petit ma1 epilepsy. The tottering mouse has a slight ataxia, concomitant with tremor and absence seizures [18,22]. In rats containing the autosomal recessive mutations zitter and tremor, seizures have been charac- terized and determined to include tonic convulsions. Absence-like seizures occurring during immobility in these rats were associated with the onset or the offset of tonic seizures [25]. The histology on these rats showed spongy degeneration of the cerebellum, specifically of granule and Purkinje cells, as well as neuronal degeneration in the thalamus and the reticular formation [24,25].

Abnormal noradrenergic innervation of the cerebellar cortex have been observed in several rodent strains with genetic mutations that have a high incidence of spike and wave discharges, including the tottering, reeler and staggerer mice [I 8,22,24].

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Some of these changes include hyperinnervation of

the Purkinje cell layer and an increased sensitivity

of Purkinje cells to the neuromodulatory effects of

norepinepherine [ 11,13,20]. The abnormalities of

noradrenergic innervation may be especially im-

portant in the present context, since neurons in

the locus coeruleus fire phase-locked with HVS

(Berrige, Foote and Buzsaki, unpublished observa-

tions). The altered responsiveness of the cerebel-

lum arising from the widespread modulation of

the noradrenergic fibers may result in excessive

rhythmic output of the cerebellum. It may, there-

by, be causally related to the occurrence of exces-

sive thalamic rhythmicity underlying HVS in the

affected rodent strains.

This study has demonstrated that cerebellar neu-

rons are entrained in rhythmic bursts during HVS

in rats with a high incidence of spike-and-wave

patterns. Such correlations were reliably observed

in both WAG and F344/BN rats. Putative Purkinje

cells fired predominantly during the spike compo-

nent of HVS. It is logical to assume that neurons

that discharged on the spike and wave components

of HVS, respectively, were inhibited by each other.

However, such a statement requires independent

physiological identification of neurons in future

studies.

Excessive oscillation of the thalamic network

may result from a single or from several subtle

alterations, including ion channel or receptor

changes of thalamic neurons, increased inhibition

of thalamocortical cells by the extrapyramidal in-

put or alteration of cellular responsivity to cate-

cholamines [5,6]. The present findings suggest that

increased rhythmic excitation by the cerebellotha-

lamic pathway may also be an important factor.

Our final comment concerns the physiological

role of the cerebellar input in thalamic oscillation.

It is logical to assume that if the cerebellar feed-

back is important in the generation of spike-and-

wave (absence) epilepsy, then the cerebellothalamic

pathway would play a similar role in the mainte-

nance of physiological oscillations, such as sleep

spindles [19,26], and pathologic states, such as Par-

kinsonian tremor [6]. Such a reasoning is sup-

ported by previous observations that barbiturate

spindles can be converted to spike-and-wave pat-

terns in the penicillin model of absence epilepsy

[19]. Nevertheless, such a hypothesis requires the

demonstration of the entrainment of cerebellar

neurons by naturally occurring sleep spindles and

tremor, independent of the occurrence of necorti-

cal HVS.

Acknowledgements

The authors wish to thank Dr. Lasse Raisanen of

the University of Kuopio, Finland, for the kind

gift of the electrothermomechanical film (ETMF)

device with which our movement recordings were

made. The procedure for manufacturing ETMF is

held by Kari Khirjavainen (U.S. Patent, no.

4654546, 1987). We also thank Dr. J.L. Noebels

for discussions and Melissa Hsu for helping with

the histology. This work was supported by

NINDS (NS-27058, 28121) and the Whitehall

Foundation.

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Cerebellar neuronal activity correlates with spike and wave EEG patterns in the rat