Role of the Chloride co-transporter NKCC1 in excitability of dentate Gyrus in chorinic epilepsy

Abstract

Granule cells of the dentate gyrus (GCDG) are the gatekeepers of the tri-synaptic hippocamapal circuit in part by an intrinsically low cell excitability, which is pathologically increased in Temporal Lobe Epilepsy. Alterations in the delicate balance between excitation and inhibition in the nervous system is involved in several neurological conditions. g-amino butyric acid (GABA) is the most important inhibitory neurotransmitter in the nervous system, however excitatory effects have been observed in GCDG in epileptic patients. This is produced by an outward flux of chloride ions, whose pathological intracellular concentration is mediated by the activity of the Sodium Potassium co-Transporter 1 (NKCC1), which accumulates chloride in the cell. The expression of this transporter is very low in mature brain, showing a decrease in expression for born to virtually no detection at P18. In light of this evidence, we wanted to study how intracellular chloride levels and NKCC1 expression alter the circuit excitability in mature GCDG, in order to understand the role of this co-transporter in both normal and epileptic neurons for a possible use as anti-epileptic drug. Here we show by extracellular field potentials recordings of acute hippocampal slices of adult animals that application of the selective NKCC1 inhibitor Bumetanide produces a decrease in circuit excitability in synaptic and population spike signals of both control and epileptic animals. In summary, these results show that NKCC1 is functionally expressed in mature neurons, and careful investigation of its function should be performed before its use as anti-epilpetic drug.