Veterinary and Biomedical Sciences, Department of


Date of this Version



Neuroscience. 2010 February 17; 165(4): 1519. doi:10.1016/j.neuroscience.2009.11.040.


Copyright © 2009 IBRO. Published by Elsevier Ltd. All rights reserved. Used by permission.


The suprachiasmatic nucleus (SCN) is a circadian oscillator and biological clock. Cell-to-cell communication is important for synchronization among SCN neuronal oscillators and the great majority of SCN neurons use γ-aminobutyric acid (GABA) as a neurotransmitter, the principal inhibitory neurotransmitter in the adult central nervous system. Acting via the ionotropic GABAA receptor, a chloride ion channel, GABA typically evokes inhibitory responses in neurons via Cl− influx. Within the SCN GABA evokes both inhibitory and excitatory responses although the mechanism underlying GABA-evoked excitation in the SCN is unknown. GABA-evoked depolarization in immature neurons in several regions of the brain is a function of intracellular chloride concentration, regulated largely by the cation-chloride cotransporters NKCC1 (for chloride entry) and KCC1-4 (for chloride egress). It is well established that changes in the expression of the cation-chloride cotransporters through development determines the polarity of the response to GABA. To understand the mechanisms underlying GABA-evoked excitation in the SCN, we examined the SCN expression of cationchloride cotransporters. Previously we reported that the K+/ Cl cotransporter KCC2, a neuron-specific chloride extruder conferring GABA's more typical inhibitory effects, is expressed exclusively in vasoactive intestinal peptide (VIP) and gastrinreleasing peptide (GRP) neurons in the SCN. Here we report that the K+/Cl cotransporter isoforms KCC4 and KCC3 are expressed solely in vasopressin (VP) neurons in the SCN whereas KCC1 is expressed in VIP neurons, similar to KCC2. NKCC1 is expressed in VIP, GRP and VP neurons in the SCN as is WNK3, a chloride-sensitive neuron-specific serine-threonine kinase which modulates intracellular chloride concentration via opposing actions on NKCC and KCC cotransporters. The heterogeneous distribution of cation-chloride cotransporters in the SCN suggests that Cl levels are differentially regulated within VIP/GRP and VP neurons. We suggest that GABA's excitatory action is more likely to be evoked in VP neurons that express KCC4.