Abstracts

Focal cortical dysplasia (FCD) is increasingly recognized as an underlying pathology in patients with medically intractable epilepsy. In rodent models of brain malformation, alterations in GABA-mediated inhibition have been demonstrated (Zhu and Roper, 2000; Calcagnotto et al. 2002). Although human dysplastic cortex can be hyperexcitable, little is known about the function of this tissue. For example, whether altered inhibition contributes to the intrinsic epileptogenicity of dysplastic cortex is unknown. Here we examined inhibitory postsynaptic current (IPSC), interneuron distribution and GABA-transporter (GAT) expression in neocortical tissue samples obtained from patients with medically intractable epilepsy and FCD. Neocortical samples were obtained from patients who underwent surgery for refractory epilepsy and FCD (n = 7; age: 17-39 y.o.) or mesial temporal lobe epilepsy (MTLE) (n = 9; age: 18-39 y.o.). Visualized whole-cell voltage-clamp recordings were performed on cortical slices. Slices were perfused with nACSF containing 10 [mu]M DNQX/50 [mu]M APV. Spontaneous, miniature and evoked IPSCs (sIPSC, mIPSC and eIPSC) were recorded from dysplastic cells (FCD) and control neocortical pyramidal cells (MTLE). Control tissue is classified as [quot]normal[quot] based on MRI, ECoG and histopathologic examination. Immunostaining was performed using antibodies against calbindin, parvalbumin, GAD 65/67, GAT-1 and GAT-3. All studies were performed under guidelines of the UCSF Committee on Human Research. Synaptic inhibition was significantly reduced in regions of FCD. Analysis of sIPSC frequency revealed a reduction of 55% (1.4 [plusmn] 0.2 Hz in FCD vs. 3.1 [plusmn] 0.3 Hz in controls). For mIPSCs these values were 1.4 [plusmn] 0.3 Hz in FCD versus 2.9 [plusmn] 0.5 Hz in controls. Analysis of GABA current charge transfer confirmed this reduction. Immunostaining revealed an abnormal distribution of interneurons throughout dysplastic cortex; some areas contained small clusters of interneurons while in many regions calbindin- and parvalbumin-positive cells were scarce. In contrast to findings of reduced inhibition, sIPSC decay time constants were increased by 67% and eIPSC decay time constants by 180% on dysplastic neurons compared with controls. Application of a GABA transport inhibitor, NO-711 (50 [mu]M), prolonged eIPSC decay kinetics of control cells but had no effect on dysplastic neurons. Expression of GAT-1 and GAT-3 were decreased in FCD tissue. Here we demonstrate that GABAergic inhibition is altered in regions of FCD. These changes include (a) reduction in IPSC frequency; (b) alteration in IPSC decay kinetics and GABA re-uptake; (c) scattering of GABAergic interneurons across dysplastic cortex and (d) reduction in GAT expression. These findings provide a new perspective on the epileptogenic process in a dysplastic brain.