Increased pyramidal excitability and NMDA conductance can explain posttraumatic epileptogenesis without disinhibition: A model

Increased pyramidal excitability and NMDA conductance can explain posttraum atic epileptogenesis without disinhibition: a model. J. Neurophysiol. 82. 1 748-1758, 1999. Partially isolated cortical islands prepared in vivo become epileptogenic within weeks of the injury. In this model of chronic epilept ogenesis, recordings from cortical slices cut through the injured area and maintained in vitro often show evoked, long- and variable-latency multiphas ic epileptiform field potentials that also can occur spontaneously. These e vents are initiated in layer V and are synchronous with polyphasic long-dur ation excitatory and inhibitory potentials (currents) in neurons that may l ast several hundred milliseconds. Stimuli that are significantly above thre shold for triggering these epileptiform events evoke only a single large ex citatory postsynaptic potential (EPSP) followed by an inhibitory postsynapt ic potential (IPSP). We investigated the physiological basis of these event s using simulations of a layer V network consisting of 500 compartmental mo del neurons, including 400 principal (excitatory) and 100 inhibitory cells. Epileptiform events occurred in response to a stimulus when sufficient N-m ethyl-D-aspartate (NMDA) conductance was activated by feedback excitatory a ctivity among pyramidal cells. In control simulations this activity was pre vented by the rapid development of IPSPs. One manipulation that could give rise to epileptogenesis was an increase in the threshold of inhibitory inte rneurons. However, previous experimental data from layer V pyramidal neuron s of these chronic epileptogenic lesions indicate: upregulation, rather tha n 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 co ntacts, which would increase recurrent EPSPs from one cell onto another. Co nsistent with this, we found that increasing the excitability of pyramidal cells and the strength of NMDA conductances, in the face of either unaltere d or increased inhibition, resulted in generation of epileptiform activity that had characteristics similar to those of the experimental data. Thus ep ileptogenesis such as occurs after chronic cortical injury can result from alterations of intrinsic membrane properties of pyramidal neurons together with enhanced NMDA synaptic conductances.