Chronic focal neocortical epileptogenesis: Does disinhibition play a role?

Abstract

Several lines of evidence have suggested that decreases in postsynaptic inhibition may have a role in epileptogenesis in cortical structures. However, other studies have suggested that GABAergic inhibition is spared, or even augmented in some forms of post-lesional epilepsy. In the studies described here, inhibitory events were recorded in two models of post-lesional chronic epileptogenesis. (i) As previously reported (D.A. Prince and G.-F. Tseng. J. Neurophysiol. 69: 1276-1291. 1993), epileptiform activity develops in slices from partially isolated rat neocortical islands 2-3 weeks after the initial in vivo lesion. In this model of post-traumatic epilepsy, large amplitude polyphasic inhibitory postsynaptic currents (IPSCs) in layer V pyramidal neurons are associated with each interictal epileptiform field potential. The frequency of spontaneous IPSCs as well as miniature IPSCs was significantly increased in neocortical slices from the epileptogenic chronically injured cortex versus controls. Immunocytochemical reactions for parvalbumin and calbindin, calcium binding proteins present in subgroups of GABAergic neurons, showed an increased staining of both neuropil and somata within the epileptogenic tissue. Immunoreactivity for glutamic acid decarboxylase (GAD) and GABA also appeared to be increased in the neuropil. (ii) Cortical microgyri resembling human malformations were produced by freeze lesions made transcranially in P0 rat cortex (K.M. Jacobs, M.J. Gutnick, and D.A. Prince. Cereb. Cortex, 6: 514-523. 1996). The boundary between the four-layered microgyrus and surrounding cortex become epileptogenic within about 2 weeks, as judged by evoked extracellular field potentials and cellular activities. Epileptogenesis in the surrounding cortex is not altered when the microgyrus itself is isolated by transcortical cuts. Patch-clamp recordings from layer V neurons in the epileptogenic zone showed that spontaneous IPSCs are larger and more dependent on glutamatergic synapses than in control neurons. The amplitudes of polysynaptic IPSCs evoked by threshold stimulation were also larger than in control cells. Although evaluation of inhibitory events in these models is still incomplete, results to date suggest that GABAergic inhibition may be enhanced in epileptogenic areas associated with chronic cortical injury. Sprouting of axonal arborizations of pyramidal cells onto interneurons, upregulation of GABAergic neurons, and perhaps sprouting of inhibitory axons that make increased numbers of contacts onto pyramidal cells may all contribute to the increased inhibitory drive. Results in these models do not support the disinhibitory hypothesis of chronic epileptogenesis.

Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex

“…The enhanced glutamatergic excitation in the cortices treated with higher concentrations of the GABA-A receptor antagonist suggests that inhibitory transmission was sufficient to partially suppress enhanced excitation. These findings concur with those of previous anatomical studies of the chronically injured cortex that show an increase in symmetrical synapses on dendritic shafts (Rutledge, 1978), and with physiological studies that show an increase in inhibitory synaptic currents in layer V pyramidal neurons (Prince et al, 1997). In contrast, a recent quantitative study on the chronically injured cortex showed an increase in the ratio between the AMPA-KA receptor-mediated excitation and GABA-A receptor-mediated inhibition (Li and Prince, 2002).…”

Slow State Transitions of Sustained Neural Oscillations by Activity-Dependent Modulation of Intrinsic Excitability

“…Traditionally, the role of inhibitory interneurons is to maintain reasonable firing frequency levels, and a shift in the balance between excitation and inhibition toward excitation is often associated with epileptic states (Dichter and Ayala, 1987;Tasker and Dudek, 1991;Galarreta and Hestrin, 1998;Nelson and Turrigiano, 1998). A number of studies conclude, however, that synaptic inhibition remains functional in many forms of paroxysmal activities (Higashima, 1988;Davenport et al, 1990;Traub et al, 1996;Esclapez et al, 1997;Prince et al, 1997;Cohen et al, 2002;Timofeev et al, 2002;Engel et al, 2003;Topolnik et al, 2003). In agreement with these findings, the role of inhibition is rather subtle in our model.…”

Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures

“…In a mathematical model of layer V cortical neurons, Bush et al (1999) ''induced'' epileptiform activity by increasing pyramidal cell excitability, which was often paralleled by increased perisomatic inhibition. Increased inhibition was actually observed experimentally in postlesional epileptogenic slices (Prince et al, 1997) supporting the ''counterintuitive'' hypothesis of increased inhibition facilitating ictogenesis. This is in line with previous findings that GABA or GABA-enhancing substances can induce epileptiform activity (Kaila et al, 1997;Lopantsev and Avoli, 1998).…”