The cation-chloride cotransporter NKCC1 promotes sharp waves in the neonatal rat hippocampus

• Published in: The Journal of physiology Vol. 573; no. 3; pp. 765 - 773
• Main Authors: Sipilä, Sampsa T., Schuchmann, Sebastian, Voipio, Juha, Yamada, Junko, Kaila, Kai
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15-06-2006; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: Action Potentials; Animals; Animals, Newborn; Bumetanide - pharmacology; GABA-A Receptor Agonists; gamma-Aminobutyric Acid - pharmacology; Hippocampus - drug effects; Hippocampus - growth & development; Hippocampus - metabolism; Interneurons - drug effects; Interneurons - metabolism; Nerve Net - drug effects; Nerve Net - growth & development; Nerve Net - metabolism; Neuroscience; Pyramidal Cells - drug effects; Pyramidal Cells - metabolism; Rats; Rats, Wistar; Receptors, GABA-A - metabolism; Sodium Potassium Chloride Symporter Inhibitors - pharmacology; Sodium-Potassium-Chloride Symporters - metabolism; Solute Carrier Family 12, Member 2; Synaptic Transmission
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2006.107086

Earlier studies indicate a crucial role for the interconnected network of intrinsically bursting CA3 pyramidal neurons in
the generation of in vivo hippocampal sharp waves (SPWs) and their proposed neonatal in vitro counterparts, the giant depolarizing potentials (GDPs). While mechanisms involving ligand- and voltage-gated channels have
received lots of attention in the generation of CA3 network events in the immature hippocampus, the contribution of ion-transport
mechanisms has not been extensively studied. Here, we show that bumetanide, a selective inhibitor of neuronal Cl − uptake mediated by the Na + –K + –2Cl − cotransporter isoform 1 (NKCC1), completely and reversibly blocks SPWs in the neonate (postnatal days 7–9) rat hippocampus
in vivo , an action also seen on GDPs in slices (postnatal days 1–8). These findings strengthen the view that GDPs and early SPWs
are homologous events. Gramicidin-perforated patch recordings indicated that NKCC1 accounts for a large (∼10 mV) depolarizing
driving force for the GABA A current in the immature CA3 pyramids. Consistent with a reduction in the depolarization mediated by endogenous GABA A -receptor activation, bumetanide inhibited the spontaneous bursts of individual neonatal CA3 pyramids, but it slightly increased
the interneuronal activity as seen in the frequency of spontaneous GABAergic currents. An inhibitory effect of bumetanide
was seen on the in vitro population events in the absence of synaptic GABA A receptor-mediated transmission, provided that a tonic GABA A receptor-mediated current was present. Our work indicates that NKCC1 expressed in CA3 pyramidal neurons promotes network
activity in the developing hippocampus.