Nkcc1 Inhibition Decrease Altered Excitability Of Dentate Gyrus In Adult Epileptic Conditions

Abstract

Granule cells of the dentate gyrus (GCDG) are the gatekeepers of hippocampal circuit by an intrinsically low cell excitability, which is pathologically increased in Temporal Lobe Epilepsy. Alterations in balance between excitation and inhibition in the nervous system are involved in several neurological conditions. γ-amino butyric acid (GABA) is the most important inhibitory neurotransmitter in the nervous system, however excitatory effects produced by this neurotransmitter have been observed in GCDG in epileptic patients. In this work, we wanted to study how intracellular chloride levels driven by Na+ K+ Cl- co-Transporter 1 (NKCC1) expression alter the circuit excitability in mature GCDG. Here, we show by extracellular field recordings of hippocampal slices the glutamatergic and GABAergic response, this by perforant path stimulation and granulare stimulation respectively. Application of NKCC1 inhibitor –Bumetanide– produces a ~50% decrease in circuit excitability in synaptic and population spike signals of epileptic animals. Furthermore, the GABAergic responses also decrease ~40%. However, only 10% decrease in glutamatergic and GABArrgic response was observed in control slices. These results suggest that NKCC1 has a low expression in mature tissue, but its expression increases in epileptic tissues, being responsible of the increase in excitability. This work is highly relevant because suggest a new pharmacological target for patients who do not respond to conventional treatments.