The Journal of Neurophysiology Vol. 82 No. 4 October 1999, pp. 1748-1758
Copyright ©1999 by the American Physiological Society

Increased Pyramidal Excitability and NMDA Conductance Can Explain Posttraumatic Epileptogenesis Without Disinhibition: A Model

 ¹Department of Physiology,  ²Department of Otolaryngology,  ³W.M. Keck Center for Integrative Neuroscience, and  ⁴Sloan Center for Theoretical Neurobiology, University of California, San Francisco, California 94143-0444; and  ⁵Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305

Bush, Paul C., David A. Prince, and Kenneth D. Miller. Increased Pyramidal Excitability and NMDA Conductance Can Explain Posttraumatic Epileptogenesis Without Disinhibition: A Model. J. Neurophysiol. 82: 1748-1758, 1999. Partially isolated cortical islands prepared in vivo become epileptogenic within weeks of the injury. In this model of chronic epileptogenesis, recordings from cortical slices cut through the injured area and maintained in vitro often show evoked, long- and variable-latency multiphasic epileptiform field potentials that also can occur spontaneously. These events are initiated in layer V and are synchronous with polyphasic long-duration excitatory and inhibitory potentials (currents) in neurons that may last several hundred milliseconds. Stimuli that are significantly above threshold for triggering these epileptiform events evoke only a single large excitatory postsynaptic potential (EPSP) followed by an inhibitory postsynaptic potential (IPSP). We investigated the physiological basis of these events using simulations of a layer V network consisting of 500 compartmental model neurons, including 400 principal (excitatory) and 100 inhibitory cells. Epileptiform events occurred in response to a stimulus when sufficient N-methyl-D-aspartate (NMDA) conductance was activated by feedback excitatory activity among pyramidal cells. In control simulations, this activity was prevented by the rapid development of IPSPs. One manipulation that could give rise to epileptogenesis was an increase in the threshold of inhibitory interneurons. However, previous experimental data from layer V pyramidal neurons of these chronic epileptogenic lesions indicate: upregulation, rather than downregulation, of inhibition; alterations in the intrinsic properties of pyramidal cells that would tend to make them more excitable; and sprouting of their intracortical axons and increased numbers of presumed synaptic contacts, which would increase recurrent EPSPs from one cell onto another. Consistent with this, we found that increasing the excitability of pyramidal cells and the strength of NMDA conductances, in the face of either unaltered or increased inhibition, resulted in generation of epileptiform activity that had characteristics similar to those of the experimental data. Thus epileptogenesis such as occurs after chronic cortical injury can result from alterations of intrinsic membrane properties of pyramidal neurons together with enhanced NMDA synaptic conductances.