Receptors with low affinity for neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic animals

Karthik Rajasekaran, Suchitra Joshi, Chengsan Sun, Zakaria Mtchedlishvilli, Jaideep Kapur

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Neurosteroid sensitivity of GABAA receptor mediated inhibition of the hippocampal dentate granule cells (DGCs) is reduced in animal models of temporal lobe epilepsy. However, the properties and subunit composition of GABAA receptors mediating tonic inhibition in DGCs of epileptic animals have not been described. In the DGCs of epileptic animals, allopregnanolone and L-655708 sensitivity of holding current was diminished and δ subunit was retained in the endoplasmic reticulum and its surface expression was decreased the in the hippocampus. Ro15-4513 and lanthanum had distinct effects on holding current recorded from DGCs of control and epileptic animals suggesting that the pharmacological properties of GABAA receptors maintaining tonic inhibition in DGCs of epileptic animals were similar α4ΒxΓ2 subunits. Furthermore, surface expression of the α4 subunit increased and a larger fraction of the subunit co-immunoprecipitated with theΓ2 subunit in hippocampi of epileptic animals. Together, these studies revealed that functional αα4ΒxΓ and α5ΒxΓ2 receptors were reduced in the hippocampi of epileptic animals and that novel α4bxΓ2 receptors contributed to the maintenance of tonic inhibition. The presence of α4ΒxΓ2 receptors resulted in low GABA affinity and neurosteroid sensitivity of tonic currents in the DGCs of epileptic animals that could potentially increase seizure vulnerability. These receptors may represent a novel therapeutic target for anticonvulsant drugs without sedative actions.

Original languageEnglish (US)
Pages (from-to)490-501
Number of pages12
JournalNeurobiology of Disease
Volume40
Issue number2
DOIs
StatePublished - Nov 2010

Fingerprint

gamma-Aminobutyric Acid
Neurotransmitter Agents
GABA-A Receptors
Hippocampus
L 655,708
Pregnanolone
Lanthanum
Temporal Lobe Epilepsy
Hypnotics and Sedatives
Endoplasmic Reticulum
Anticonvulsants
Seizures
Animal Models
Maintenance
Pharmacology

Keywords

  • Dentate granule cells
  • GABA-A receptor
  • Neurosteroids
  • Temporal lobe epilepsy
  • Tonic inhibition

ASJC Scopus subject areas

  • Neurology

Cite this

Receptors with low affinity for neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic animals. / Rajasekaran, Karthik; Joshi, Suchitra; Sun, Chengsan; Mtchedlishvilli, Zakaria; Kapur, Jaideep.

In: Neurobiology of Disease, Vol. 40, No. 2, 11.2010, p. 490-501.

Research output: Contribution to journalArticle

Rajasekaran, Karthik ; Joshi, Suchitra ; Sun, Chengsan ; Mtchedlishvilli, Zakaria ; Kapur, Jaideep. / Receptors with low affinity for neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic animals. In: Neurobiology of Disease. 2010 ; Vol. 40, No. 2. pp. 490-501.
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