Neonatal inhibition of Na+-K+-2Cl--cotransporter prevents ketamine induced spatial learning and memory impairments.
Prolonged ketamine exposure in neonates at anesthetic doses is known to cause long-term impairments of learning and memory. A current theoretical mechanism explains this phenomenon as being neuro-excitotoxicity mediated by compensatory upregulation of N-methyl-d-aspartate receptors (NMDARs), which then initiates widespread neuroapoptosis. Additionally, the excitatory behavior of GABAergic synaptic transmission mediated by GABAAreceptors (GABAARs), occurring during the early neuronal development period, is proposed as contributing to the susceptibility of neonatal neurons to ketamine-induced injury. This is due to differential developmental expression patterns of Na+-K+-2Cl-co-transporter (NKCC1) and K+-Cl-co-transporter. Studies have shown that bumetanide, an NKCC1 inhibitor, allows neurons to become inhibitory rather than excitatory early in development. We thus hypothesized that bumetanide co-administration during ketamine treatment would reduce over excitation and protect the neurons from excitotoxicity. In this initial study, the Morris Water Maze test was used to assess the effects of co-administration of ketamine and bumetanide to neonatal Sprague-Dawley rats on long-term learning and memory changes seen later in life. It was revealed that bumetanide, when co-treated with ketamine neonatally, significantly impeded behavioral deficits typically seen in animals exposed to ketamine alone. Therefore, these findings suggest a new mechanism by which neonatal ketamine induced learning impairments can be prevented.
Department of Biology, College of Science, The University of Texas at Arlington, Arlington, TX, USA.
Ryan A
RA
Stevens
Department of Biology, College of Science, The University of Texas at Arlington, Arlington, TX, USA.
Brandon D
BD
Butler
Department of Psychology, College of Science, The University of Texas at Arlington, Arlington, TX, USA.
Saurabh S
SS
Kokane
Department of Psychology, College of Science, The University of Texas at Arlington, Arlington, TX, USA.
Andrew W
AW
Womack
Department of Psychology, College of Science, The University of Texas at Arlington, Arlington, TX, USA. Electronic address: qilin@uta.edu.
Qing
Q
Lin
D000818:Animals; D000831:Animals, Newborn; D002034:Bumetanide / Q000494:pharmacology*; D004338:Drug Combinations; D005260:Female; D007649:Ketamine / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D064506:Solute Carrier Family 12, Member 2 / Q000187:drug effects*; D065853:Spatial Learning / Q000187:drug effects*
D004338:Drug Combinations; C578879:Slc12a2 protein, rat; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D007649:Ketamine
Anesthetic; Bumetanide; GABA(A)R; Ketamine; NKCC1; Neurotoxicity