Chloride Co-Transporters In Neuropsychiatric Disorders

Abstract

GABA is the main inhibitory neurotransmitter in the nervous system, which opens Cl- selective channels. Depending on the intracellular Cl- concentration, the ion flux could cause either inhibitory or excitatory effects. In immature neurons elevated Cl- is due to the action of Na+ K+ Clco- transporter 1 (NKCC1), which is observed in some types of epilepsy, causing that antiepileptic drugs do not decrese excitability, and in some cases increase seizure frequency. Recent evidence suggest that in schizophrenia, a disorder in which there is also a decrease in inhibition, there is an increase in the ratio of NKCC1/KCC2 messenger. In order to study how chloride co-transporters and Cl- levels are involved in circuit remodeling in these neuropsychiatric conditions, we study the role of NKCC1 by using behavioral, biochemical and electrophysiological techniques. In dentate gyrus of adult rats with chronic epilepsy the NKCC1-dependent component of GABAergic synaptic response is increased with respect to controls, suggesting that this co-transporter is more express in comparison to mature adults. Application of the specific NKCC1 blocker Bumetanide decrease the global circuit excitability in epileptic animals returning it to values close to control. This evidence shows that in epileptic conditions the increased excitability is produced not only by loss of GABAergic interneurons, but also by altering the Cl- driving force. In other hand, schizophrenic-like animals showed an increase in excitability of CA3-CA1 and perforant path-Dentate Gyrus synapses, but only the last one exhibit changes when NKCC1 was blocked, showing that alterations in this co-transporter are localized in the hippocampal circuit. Taken together, these results suggest that chloride homeostasis is an important physiological target to be study in terms of understanding neuro- psychiatric diseases, and might be one of the links accounting for the co-morbidity observed in patients.