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Chronic epileptogenesis studied in vitro.

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Chronic Epileptogenesis
Studied In Vitro
David A. Prince. M D
In their recent paper C43,Schwartzkroin and colleagues discuss the interpretation of intracellular recordings from normal and presumably ,abnormal in vitro neocortical slices in
relation to the occurrence of epileptiform burst discharges.
At issue is whether some aspects of the mechanisms of
chronic epileptogenesis can be studied in the in vitro slice
preparation. Robert Wong and I [ 3 ] had previously concluded that some neurons in slices from human chronic
epileptogenic foci retain abnormal properties in vitro.
Schwartzkroin and colleagues state that it is unclear to them
whether any of the bursts recorded in our experiments were
“of the all-or-none, PDS (paroxysmal depolarization shift)
type.” A careful examination of Figures 1 and 2 of our paper
shows a neuron with typical all-or-none burst properties similar to those seen in epileptogenic foci in vivo and recently
described by Gutnick and colleagues 123 in penicillin-treated
neocortical slices in vitro. These characteristics include all-ornone triggering of variable latency bursts, dependent on
stimulus parameters, and the appearance of relatively stereotyped, large-amplitude prolonged depolarizations, the occurrence of which is independent of the initial shortlatency excitatory postsynaptic potential. We were cautious
in our interpretation of such bursts, because other forms
of burst discharge can occur in normal neocortical slices
Schwartzkroin and colleagues also criticize our use of control nontemporal cortex, because most of our epileptic samples were from lateral temporal cortex. Obviously, it was
impossible to provide area-matched normal cortical controls
in a human study. W e felt fortunate to obtain biopsy material
from “normal” parietal and frontal cortex in four patients not
having seizures. By contrast, Schwartzkroin and colleagues
apparently did not obtain “normal” human cortical biopsy
material from any nonseizure patients. Instead they used a
control population obtained by retrospectively differentiating
slices from the “epileptic focus” and from tissue with a “questionable relation” to the epileptic focus on electrocorticographic and histopathological grounds (Table 2 in 141). This
approach is clearly inadequate, since recent positron emission
tomographic scan results, some of which they cite, show large
areas of hypometabolic cortex in regions remote from the
electrocorticographic focus. Other evidence sugqests that
long-term changes in excitability might occur in tissue synaptically related to areas of epileptogenesis, making it difficult
to accept electrophysiological controls from even remote
areas of the epileptogenic brain.
Although Schwartzkroin and colleagues did not record any
long- and variable-latency all-or-none bursts similar to those
Wong and I reported 131, they did record graded shortlatency burst responses in a proportion of their slices. The
recordings shown in Figures 1 B3 and 3 A5 of their paper,
from neurons of epileptogenic human and monkey cortex,
respectively, show large and prolonged orthodromic de-
polarizations associated with spike bursts and inactivation of
spike generation. In my experience such responses are rarely
seen in normal neocortical slices, and then only following
high-intensity stimulation. The one burst shown from normal
monkey cortex (Fig 3 C 4 ) has very different characteristics.
Perhaps a more careful analysis of their data and collection of
control data from normal human cortex will allow Schwartzkroin and colleagues to determine whether even the shortlatency graded burst responses they reported in epilcptogenic
tissue are signs of altered synaptic inputs, e.g., the decreased
hyperpolarizing postsynaptic potentials they appear to have
demonstrated in epileptogenic monkey cortex (Table 3 in
Selection of epileptogenic tissue for biopsy and identification of the principally involved neurons in a slice are
indeed difficult issues. In the experiments of Schwartzkroin
and colleagues, 10 Lucifer Yellow-filled neurons from monkey cortical lesions were qualitatively normal anatomically.
W e therefore assume that impaled cells were not from the
sites of gross pathology-or at least, as stated, that in preparing their slices they avoided the areas of most intense gliotic
scarring. These latter sites are known to contain neurons with
gross structural abnormalities [ 5 ] and could harbor cells with
more severe functional abnormalities.
Problems such as the disruption of connections with more
remote cortical and subcortical areas and the loss of potential
remote humoral effects on which some aspects of epileptogenesis may depend will always be with us if slice technology is used. Nevertheless, we are not as pessimistic as
Schwartzkroin and colleagues with respect to the information
obtained from studies of chronically injured tissue in vitro.
Some of their own data C41,as well as our previously published study [3] and recent work from our laboratory [2al,
suggest that some properties of neurons in such slices are
distinctly different from those in normal cortex. It is likely
that additional experiments in vitro will provide new information relevant to the mechanisms of chronic epileptogenesis.
Department of Neurology
Stanford Uniziersity Medical Center
Stanford, CA 94305
1. Connors BW, Gutnick MJ, Prince DA: Electrophysiological
properties of neocortical neurons in vitro. J Neurophysiol
48~1302-1320, 1982
2. Gutnick MJ, Connors BW, Prince DA: Mechanisms of neocortical epileptogenesis in vitro. J Neurophysiol 48:132I- 1335,
2a. Lighthall JW, Prince DA: Neuronal activity in areas of chronic
cortical injury. Neurosci Ahsrr (in press)
3 . Prince DA, Wong RKS: Human epileptic neurons studied in
vitro. Brain Res 210:323-333, 1981
4. Schwartzkroin PA, Turner DA, Knowles WD, Wyler AR: Studies of human and monkey “epileptic” neocortex in the in virro
slice preparation. Ann Neurol 13:249-257, 1983
5. Westrum LE, White LE Jr, Ward AA Jr: Morphology of
the experimental epileptic focus. J Neurosurg 2 I : 1033-1046,
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studies, epileptogenesis, vitro, chronic
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