Homeostatic Synaptic Plasticity Can Explain Post-traumatic Epileptogenesis in Chronically Isolated Neocortex

Abstract

Chronically isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of post-traumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in chronically isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in chronically isolated neocortex. These burst discharges lasted a few hundred ms, propagated at 1-3 cm/s and consisted of large (10-15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of post-traumatic epileptogenesis.

Epileptogenesis due to glia-mediated synaptic scaling

“…burst probability increase When varying the proportion of deafferentation for a fixed lesion size (15!15), the strength of remaining synapses reaches a value large enough to facilitate network bursts (figure 5b). The burst probability increases with the severity of the lesion (figure 5c), consistent with the results in Houweling et al (2005). Furthermore, the effect is observable for a wide range of partial deafferentation levels, as observed experimentally (Timofeev et al 2000).…”

“…Thus, it is plausible to assume that lesions can also enhance seizure predisposition (Timofeev et al 2000;Houweling et al 2005). In contrast to previous approaches, here we focus on the mechanism of homeostatic regulation, specifically on the spatial effects due to TNF-a diffusion.…”

Pathological Effect of Homeostatic Synaptic Scaling on Network Dynamics in Diseases of the Cortex

“…Computational models of tinnitus suggested involvement of homeostatic plasticity (Dominguez et al, 2006;Schaette and Kempter, 2006), but there has been little work that examines the role of homeostatic plasticity in more realistic, conductance-based models of cortical networks. In a previous computational modeling study (Houweling et al, 2004), cortical deafferentation was simulated to examine homeostatic plasticity as a potential cause of posttraumatic epilepsy. A recent study with cultured hippocampal slices provided additional support for this hypothesis (Trasande and Ramirez, 2007).…”

“…In contrast to this previous modeling work, we have now studied the time course of network reorganization after partial deafferentation to understand the specific roles of intact and deafferented cells as a function of time after disease onset. Because we here studied disorders of the cortex that incapacitate a presumably random fraction of neurons, the partial deafferentation scheme is different from the one used previously to investigate posttraumatic epilepsy (Houweling et al, 2004) in which all cells in the network were subject to the same degree of reduction in input.…”

“…We hypothesized (1) that the average firing rate of the network is recovered and (2) that the distribution of firing rates across cells and the fine temporal structure of the spike patterns in individual cells differ from before deafferentation. According to our hypothesis, these changes in network dynamics are attributable to the shift in balance between afferent and recurrent excitatory inputs caused by partial deafferentation (reduced afferent excitation) and synaptic scaling (increased recurrent excitation) (Houweling et al, 2004). Of particular interest is the interaction between deafferented and intact cells during this homeostatic reorganization process.…”