E.L.J.M. van Luijtelaar

Cortical and thalamic visual evoked potentials during sleep-wake states and spike-wave discharges in the rat

Flash visual evoked potentials (VEP) were simultaneously recorded from the primary visual cortex and the dorsal lateral geniculate nucleus in freely-moving WAG/Rij rats, to investigate whether the thalamic VEP shows the same state-dependent alterations as the cortical VEP. VEPs obtained during active and passive wakefulness (AW and PW), slow-wave sleep (SWS), REM sleep and during the occurrence of spike-wave discharges (SWD), a specific trait of the genetically epileptic WAG/Rij rat, were compared. The general architecture of the thalamic VEP resembles the cortical VEP, although its polarity is reversed. This facilitated the interpretation of components in terms of underlying neuronal events. The primary excitation peak is differently modulated in cortex and thalamus. Whereas the thalamic component (P30) is not affected by brain-state, the cortical component (N1) shows a strong increase in latency during SWS and SWD. In contrast, the modulation of later components is highly similar for cortex and thalamus. VEPs obtained during AW and REM resemble each other. During SWS and SWD there is a considerable, and during PW a moderate, enlargement of primarily inhibitory components. After-discharges are enhanced during SWS, SWD and REM. No evidence is found for a major impairment of sensory transmission during SWD.

Synaptology of the rostral reticular thalamic nucleus of absence epileptic WAG/Rij rats

The adult WAG/Rij rat is a well-established animal model for human absence epilepsy characterized by the presence of spike-wave discharges (SWDs). The pacemaking activity of the rostral reticular thalamic nucleus (rRTN) has been demonstrated to be essential for SWD maintenance. We investigated if SWD maintenance can be related to the synaptic organization of the rRTN, by studying the ultrastructure of the rRTN of absence epileptic WAG/Rij rats in comparison with that of non-epileptic, age-matched ACI control rats. In WAG/Rij rats, D-, L- and F-type terminals constitute the synaptic organization of the rRTN. D-type synapses, especially axo-dendritic ones, occur frequently. L- and F-type terminals are common but less frequent than D-type terminals. Semi-quantitative observations indicate that all terminal types are present on different parts of the postsynaptic neuron, but in different numbers: they are frequent on dendrites, common on somata and axons, and occur occasionally on dendritic spines. In addition, occasionally an F-type terminal was observed on the axon hillock. The three terminal types are also involved in multiple synaptic configurations, convergent as well as divergent, with dendrites, somata, axon hillocks and axons as postsynaptic structures. Convergent synaptic configurations outnumber divergent ones. The synaptic organization of the rRTN of the non-epileptic ACI rat appears to be very similar to that of the epileptic WAG/Rij rat. This indicates that SWD maintenance in the WAG/Rij rat does not depend on a different synaptic organization of the rRTN.

The role of the nucleus basalis of Meynert and reticular thalamic nucleus in pathogenesis of genetically determined absence epilepsy in rats: a lesion study.

The role of cholinergic nucleus basalis (of Meynert) and the reticular thalamic nucleus in mechanisms of the generation spontaneous spike-and-wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. Selective lesions were affected by local unilateral intraparenchymal infusions of immunotoxin 192 IgG-saporin and cholinotoxin AF64A to the nucleus basalis and the rostral pole of reticular thalamic nucleus. Injections of 192 IgG-saporin into the nucleus basalis increased the number of spontaneous SWDs, while injections in the reticular thalamic nucleus were not effective. Thereby, a loss of cholinergic activity in the nucleus basalis stimulates the appearance of SWDs. At the same time, AF64A infused into reticular thalamic nucleus, besides the reduction of choline acetyltransferase immunoreactive neurons within contralateral nucleus basalis, produced some unspecified lesion of adjacent neuronal tissue, resulted in decrease of number and duration of SWDs as well as in spectral changes in EEG. Considering that the nucleus basalis is an important source of cortical and thalamic cholinergic afferentation, we conclude that cholinergic excitatory input from this structure is important in the control of SWDs in the WAG/Rij rat model of absence epilepsy.

The multiple effects of ketamine on electroencephalographic activity and behavior in WAG/Rij rats

The effects of ketamine, a noncompetitive antagonist at the NMDA receptor, were studied on the EEG and in the open field in a genetic animal model of generalized absence epilepsy--the WAG/Rij rat strain. Animals of this strain display spontaneous occurring generalized spike-wave discharges (SWDs) in the EEG. Ketamine was systemically administered in a dose range from 3 to 30 mg/kg. Biphasic effects of ketamine were observed in the EEG. The first phase was a dose-dependent suppression of SWDs, followed by a second phase characterized by the facilitation of SWDs. This increase was expressed first as an increased number of SWDs, and later on as a significant prolongation of individual discharges and decrease in frequency of SWDs. An obvious amplitude modulation of the discharges was also found. During the period of suppression of SWDs, a new phenomenon was observed: quasi-periodic groups of spikes or wave spikes, with an internal frequency of 4-5 Hz and a periodicity of about 5 s. That quasi-periodic activity vanished a few minutes prior to the recovery of the classical SWDs. However, a specific 5-s amplitude modulation of SWDs remained present in the recovery period. The propensity of that specific ketamine-induced activity was found to be correlated with propensity of SWDs in background EEGs of drug-free animals. Ketamine also produced a dose-related initial behavioral excitation, a decrease of muscle tone in hind quarters, followed by front quarters and head, and an absence of locomotor activity. However, the time course of the behavioral changes cannot explain the effects on the EEG. It can be concluded that ketamine has more effects on the EEG than previously assumed which cannot be explained by a simple blockade of the NMDA receptor. It is proposed that the obtained specific dynamics of SWDs frequency may be caused by changes in the activity of the thalamo-cortical pacemaker that is generating SWDs.

N150 in amygdalar ERPs in the rat: Is there modulation by anticipatory fear?

The hypothesis was tested whether the amygdalar N150 of rats, a slow, negative component in the event-related potential from the lateral amygdala, is sensitive to a state of anxious anticipation. A conditioning procedure was applied in which a series of six auditory stimuli was followed by a shock when presented alone, but not when the auditory stimuli were preceded by a visual stimulus. Heart rate recordings confirmed that the auditory stimulus train induced a state of increasing anticipatory fear and that this condition was modulated by the visual stimulus. During behavioral training, a N150 appeared in the amygdalar event-related potential evoked by the auditory stimuli, replicating previous findings. However, the amplitude of the N150 was not affected by whether or not the visual stimulus had been presented before. These results failed to support the idea that the N150 is related to the expectancy of an aversive event. An alternative interpretation, emphasizing the increase in arousal and attention that is inherent to aversive learning, is discussed.

Neurotrophic ACTH4-9 analogue therapy normalizes electroencephalographic alterations in chronic experimental allergic encephalomyelitis

Chronic experimental allergic encephalomyelitis (CEAE) is an established experimental model for multiple sclerosis (MS). The demyelinating lesions in the white matter of the central nervous system observed in CEAE and in MS are accompanied by various neurophysiological alterations. Among the best defined electrophysiological abnormalities are the changes in event‐related potentials, in particular evoked potentials involving the spinal cord, i.e. motor and sensory evoked potentials. Less familiar are the changes observed in the electroencephalogram of CEAE‐affected animals, which are also encountered in the human equivalent, MS. In the present experiment we evaluated the therapeutic value of a neurotrophic peptide treatment [H‐Met(O2)‐Glu‐His‐Phe‐d‐Lys‐Phe‐OH, an ACTH4–9 analogue] and its effect on the delayed flash visual evoked potentials (VEP) and power spectra of the electroencephalogram, during a 17‐week follow‐up of CEAE. CEAE animals treated with the neurotrophic peptide were protected against the development of neurological symptoms during the course of the demyelinating syndrome. VEPs of animals suffering from CEAE showed a delay of the latencies of the late components which was significantly counteracted by peptide treatment. The peak‐to‐peak amplitude of the VEP afterdischarge recorded from CEAE animals was significantly increased during the course of CEAE and correlated closely with the progression of the myelinopathy. Furthermore, CEAE animals showed an increase of electroencephalogram (EEG) beta activity of up to 500% as compared with the age‐matched control group. This increase in beta power mainly consisted of a prevailing 20–21u2003Hz peak, a frequency that normally is not dominant in control EEG recordings of the rat during passive wakefulness. All these electrophysiological phenomena were absent in ACTH4–9 analogue‐treated animals. The present findings underscore the potential importance of a neurotrophic peptide treatment in the pharmacotherapy of central demyelinating syndromes, and possibly of MS.