THE ROLE OF THE PIRIFORM CORTEX IN KINDLING

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Abstract

In epilepsy research, there is growing interest in the role of the piriform cortex (PC) in the development and maintenance of limbic kindling and other types of limbic epileptogenesis leading to complex partial seizures, i.e. the most common type of seizures in human epilepsy. The PC (“primary olfactory cortex”) is the largest area of the mammalian olfactory cortex and receives direct projections from the olfactory bulb via the lateral olfactory tract (LOT). Beside the obvious involvement in olfactory perception and discrimination, the PC, because of its unique intrinsic associative fiber system and its various connections to and from other limbic nuclei, has been implicated in the study of memory processing, spread of excitatory waves, and in the study of brain disorders such as epilepsy with particular emphasis on the kindling model of temporal lobe epilepsy with complex partial seizures. The interest in the kindling model is based primarily on the following observations. (1) the PC contains the most susceptible neural circuits of all forebrain regions for electrical (or chemical) induction of limbic seizures. (2) During electrical stimulation of other limbic brain regions, broad and large afterdischarges can be observed in the ipsilateral PC, indicating that the PC is activated early during the kindling process. (3) The interictal discharge, which many consider to be the hallmark of epilepsy, originates in the PC, independent of which structure serves as the kindled focus. (4) Autoradiographic studies of cerebral metabolism in rat amygdala kindling show that, during focal seizures, the area which exhibits the most consistent increase in glucose utilization is the ipsilateral paleocortex, particularly the PC. (5) During the commonly short initial afterdischarges induced by stimulation of the amygdala at the early stages of kindling, the PC is the first region that exhibits induction of immediate-early genes, such as c-fos. (6) The PC is the most sensitive brain structure to brain damage by continuous or frequent stimulation of the amygdala or hippocampus. (7) Amygdala kindling leads to a circumscribed loss of GABAergic neurons in the ipsilateral PC, which is likely to explain the increase in excitability of PC pyramidal neurons during kindling. (8) Kindling of the amygdala or hippocampus induces astrogliosis in the PC, indicating neuronal death in this brain region. Furthermore, activation of microglia is seen in the PC after amygdala kindling. (9) Complete bilateral lesions of the PC block the generalization of seizures upon kindling from the hippocampus or olfactory bulb. Incomplete or unilateral lesions are less effective in this regard, but large unilateral lesions of the PC and adjacent endopiriform nucleus markedly increase the threshold for induction of focal seizures from stimulation of the basolateral amygdala (BLA) prior to and after kindling, indicating that the PC critically contributes to regulation of excitability in the amygdala. (10) Potentiation of GABAergic neurotransmission in the PC markedly increases the threshold for induction of kindled seizures via stimulation of the BLA, again indicating a critical role of the PC in regulation of seizure susceptibility of the amygdala. Microinjections of NMDA antagonists or sodium channel blockers into the PC block seizure generalization during kindling development. (11) Neurophysiological studies on the amygdala-PC slice preparation from kindled rats showed that kindling of the amygdala induces long-lasting changes in synaptic efficacy in the ipsilateral PC, including spontaneous discharges and enhanced susceptibility to evoked burst responses. The epileptiform potentials in PC slice preparations from kindled rats seem to originate in neurons at the deep boundary of PC. Spontaneous firing and enhanced excitability of PC neurons in response to kindling from other sites is also seen in vivo, substantiating the fact that kindling induces long-lasting changes in the PC comparable to abnormalities seen in primary foci. Taken together, these observations indicate that the PC might be part of an epileptic network which is pivotal in the genesis of kindling, facilitating and intensifying the spread of seizures from a focus in amygdala or hippocampus to cortical and subcortical regions along pathways that also are utilized in normal movements. Although direct evidence implicating the PC in the pathogenesis of human epilepsy is not yet available, the experimental data reviewed in this paper should initiate clinical studies on the potential role of this brain structure as a pacemaker or secondary focus in TLE and other types of epilepsy. Copyright © 1996 Elsevier Science Ltd.

Section snippets

INTRODUCTION

The piriform cortex (PC) is the largest area of the mammalian olfactory cortex which is characterized by direct input from the olfactory bulb (see review by Shipley et al., 1995). The PC extends over a considerable distance of the lateral and ventral surface of the rat forebrain [Fig. 1(A)]. In the literature, “primary olfactory cortex” (because the PC receives the main projection from the olfactory bulb) or “prepiroform cortex” have been used as a synonym for the PC (for discussion, see

FUNCTIONAL ANATOMY OF THE PC

The PC of the rat extends over an anterior-posterior distance of some 5 mm at the rostral and lateral surface of the forebrain just ventral to the rhinal fissure (Paxinos and Watson, 1986). Although the cell layers and morphology are generally similar in the whole PC, it is sometimes divided into an anterior and a posterior part. The borderline between anterior and posterior PC is defined tentatively by the disappearance of the lateral olfactory tract (LOT) on the PC surface and a concomitant

SPECIAL PHYSIOLOGICAL FEATURES OF THE PC

The PC has gained some attention because of striking differences in information processing and simplicity of microcircuitry, compared to neocortical areas. In contrast to the topic projection usually found in neocortical connections, the input to the PC is rather diffuse. Anatomical studies have shown that fibers from the olfactory bulb have a broad terminal field with many en passant synapses (Devor, 1976; Ojima et al., 1984). Accordingly, the representation of physiological (odors) or

Epilepsy, Epileptic Seizures, and the Kindling Model of Epilepsy

Epilepsy or the epilepsies are common disorders of the brain affecting at least 50 million people worldwide. Clinically, the epilepsies are characterized by recurrent epileptic seizures, either convulsive or non-convulsive, which are caused by partial or generalized epileptogenic discharges in the brain. Basic research on the various types of epilepsy focuses on the cellular and molecular mechanisms of the ways in which epileptic attacks inherently start, regenerate, arrest spontaneously, or

CONCLUSIONS

Several clinical and experimental studies have demonstrated that the structures of the limbic system show a low threshold for generation of epileptic activity. Unlike other cortical areas, the limbic (“temporal”) lobe shows a highly directional organization of the corticocortical association fiber system. Olfactory cortex pyramidal neurons project through a rostral-to-caudal-directed associative fiber system all over the PC and entorhinal cortex (Haberly and Price, 1978). Although it had been

Acknowledgements

Supported in part by grants from the Deutsche Forschungsgemeinschaft. We thank Dr Holger Lehmann for help in providing illustrations on GABA immunohistochemistry in piriform cortex, Dr Elisabeth Liebler (Department of Pathology, School of Veterinary Medicine, Germany) and Ursula Brakensiek for help with the microphotography, and Prof. Hermann Stefan (Department of Neurology, University of Erlangen-Nürnberg, Germany) for providing the MRI and helpful discussions.

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