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

• Published in: Journal of neurophysiology 1999-10, Vol.82 (4), p.1748-1758
• Main Authors: Bush, Paul C, Prince, David A, Miller, Kenneth D
• Format: Article
• Language: English
• Subjects: Animals; Cerebral Cortex - injuries; Cerebral Cortex - physiopathology; Epilepsy, Post-Traumatic - physiopathology; Excitatory Postsynaptic Potentials; gamma-Aminobutyric Acid - physiology; Humans; Models, Neurological; N-Methylaspartate - physiology; Neural Conduction; Pyramidal Cells - physiology; Receptors, AMPA - physiology; Receptors, GABA-A - physiology; Receptors, GABA-B - physiology; Receptors, N-Methyl-D-Aspartate - physiology; Synapses - physiology; Synaptic Transmission
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.1999.82.4.1748

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