Neonatal inhibition of Na+-K+-2Cl−-cotransporter prevents ketamine induced spatial learning and memory impairments

- Neonatal GABAergic excitation is proposed to enhance ketamine-induced neurotoxicity.
- Blockade of NKCC1 is proposed to cause neonatal neurons to become more inhibitory.
- Ketamine induced learning and memory deficits in neonatal animals were confirmed.
- Co-administration with bumetanide prevents ketamine-induced learning and memory deficits.
- GABAergic-excitatory synaptic signaling may be linked to ketamine's neurotoxic effect.

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 GABAA receptors (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.