GABAA receptor properties in catastrophic infantile epilepsy

Abstract

Catastrophic epilepsy due to cortical dysplasia is often intractable to anticonvulsant treatment. Many of the medications used unsuccessfully in treating this disorder are thought to exert at least a portion of their action through enhancement of inhibitory GABA A neurotransmission. In the present study, GABA A receptor properties in resected brain tissue from four infants with infantile spasms and intractable epilepsy due to cortical dysplasia were measured to determine if this clinical resistance to pharmacologic treatment correlates with alterations in receptor function. Results from epileptic cortex were compared with those from autopsy control samples. To perform these studies, we utilized the technique of injection of brain cellular membrane preparations into the Xenopus oocyte, which results in the incorporation of human GABA A receptors in their native configuration into the oocyte plasma membrane. Two-electrode voltage clamp electrophysiology analysis was then performed to assess GABA A receptor pharmacologic properties. The intrinsic properties of affinity, reversal potential, current decay, and current rundown were unchanged in the epileptic infants. Current enhancement by benzodiazepines was also unaltered, as was the response to barbiturates. However, a significant decrease was found in the degree of GABA A current enhancement by neurosteroids in the epileptic infants, along with an increase in current inhibition by zinc. These findings may contribute to the mechanisms of intractability in catastrophic infantile epilepsy due to cortical dysplasia, and suggest alternative therapeutic approaches.

Impaired maturation of cortical GABAA receptor expression in pediatric epilepsy

“…A recent electrophysiologic study of GABA A receptor currents in dissociated neurons from children with FCD revealed pharmacologic properties suggestive of lower α 1 subunit expression in cytomegalic neurons in regions of “severe” cortical dysplasia (Palmini FCD types 2A and 2B plus hemimegalencephaly), as compared with nondysplastic epileptogenic cortex and regions of “mild” cortical dysplasia (Andre et al, 2008). In our own pharmacologic study of GABA A receptor properties in four infants younger than 1 year of age with FCD 2A, responses to benzodiazepines and barbiturates were unchanged compared with age‐matched controls (Jansen et al, 2008), consistent with the preserved α 1 and γ 2 subunit expression levels in this group demonstrated in the current study. Some studies have reported a reduction in inhibitory postsynaptic current frequency in dysplastic neurons (Calcagnotto et al, 2005), whereas others have found no change (Cepeda et al, 2003, 2005).…”

Altered GABAA receptor subunit expression and pharmacology in human Angelman syndrome cortex

“…This allows analysis by standard two-electrode voltage clamp electrophysiology. The advantages and limitations of this technique are discussed in detail elsewhere [13]. Of particular note, absolute current amplitudes measured using this method do not accurately reflect those present in the source tissue; rather, this technique is ideal for determining relative receptor responses to pharmacologic manipulations [19].…”

“…Membrane isolation from an additional portion (50–300 mg) of each frozen cortical specimen was performed using the method of [19], with modifications, as detailed in [13]. Xenopus laevis oocyte collection and injection procedures were as described previously [13].…”

Mechanisms of Intrinsic Epileptogenesis in Human Gelastic Seizures with Hypothalamic Hamartoma

“…GABA A current rundown has been related to temporal lobe epilepsy [76–77] and cortical dysplasia [78]. Functional rundown has also been described in GABA-related transmembrane currents in surgically-resected HH tissue [79].…”