GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus

Abstract

The gamma amino butyric acid (GABA) transporters GAT-1 and GAT-3 were localized by immunohistochemistry in hippocampi removed for the control of medically intractable temporal lobe epilepsy (TLE). The study aimed to determine the relationship of GABA transporter expression to known patterns of hippocampal hyperexcitability and extracellular GABA levels. GAT-1 was localized in axon terminals and small neuronal cell bodies, and in non-sclerotic hippocampi was strongly expressed throughout all regions of the hippocampal formation. In the epileptogenic hippocampus exhibiting Ammon's horn sclerosis, immunoreactivity was reduced in the sclerotic regions CA3 and CA1, and around the cell bodies of dentate granule cells, but was increased along granule cell dendrites. GAT-3 was weakly expressed, if at all, in non-sclerotic hippocampi, but more prominently expressed in sclerotic hippocampi. GAT-3 expression was confined to cells resembling protoplasmic astrocytes, which were located in regions of relative neuronal sparing such as the dentate gyrus and hilus of the sclerotic hippocampus. The reduction in GAT-1 around granule cells in the sclerotic hippocampus could explain the prolonged GABA responses in this region. The loss of GAT-1 (a marker of GABAergic terminals) would also suggest a reduced GABAergic input to the granule cells, thus facilitating hyperexcitability. The increased GAT-3 expression in astrocytes in regions of relative neuronal sparing in the sclerotic hippocampus may be related to the overall low levels of extracellular GABA observed in the sclerotic hippocampus and their increased excitability.

Molecular Targets for Antiepileptic Drug Development

“…333 Studies in resected tissue from patients with complex partial seizures and hippocampal sclerosis indicate that the expression of GAT-1 is decreased, but that of GAT-3 may be increased, possibly explaining prolonged IPSCs and increased excitability reported in electrophysiological studies with this tissue. 334,335 Although the selective GAT-1 inhibitor tiagabine is a well recognized AED, GAT-2 and GAT-3 can now also be considered as potential targets.…”

Astrocytes and Epilepsy

“…The expression of GAT3 on astrocytes in the sclerotic hippocampus is increased. 24 GAT3 expression is confined to cells resembling protoplasmic astrocytes, which are located in regions of relative neuronal sparing, such as the dentate gyrus and hilus of the sclerotic hippocampus. 24 In vivo microdialysis studies in human hippocampal seizure foci have demonstrated reduced levels of extracellular GABA in the epileptogenic seizure focus during the ictal state.…”

“…24 GAT3 expression is confined to cells resembling protoplasmic astrocytes, which are located in regions of relative neuronal sparing, such as the dentate gyrus and hilus of the sclerotic hippocampus. 24 In vivo microdialysis studies in human hippocampal seizure foci have demonstrated reduced levels of extracellular GABA in the epileptogenic seizure focus during the ictal state. 18 The increased expression of GAT3 in these hippocampi may contribute to excess removal of GABA and thus reduced extracellular levels in the ictal state.…”

GABA uptake-dependent Ca 2+ signaling in developing olfactory bulb astrocytes

“…Glial GATs are also involved in pathological processes in the brain, for example, in patients with temporal lobe epilepsy, where astrocytic expression of GATs is increased (13), and inhibitors of glial GATs have anticonvulsant effects (14), indicating the involvement of glial GATs in the generation of epileptic seizures. It is not known, however, how glial GATs contribute to epileptic seizures.…”