Prolonged ketamine exposure induces enhanced excitatory GABAergic synaptic activity in the anterior cingulate cortex of neonatal rats

Experimental studies have indicated that prolonged ketamine exposure in neonates at anesthetic doses causes neuronal apoptosis, which contributes to long-term impairments of learning and memory later in life. The neuronal excitotoxicity mediated by compensatory upregulation of N-methyl-D-aspartate receptors (NMDARs) is proposed to be the underlying mechanism. However, this view does not convincingly explain why excitotoxicity-related apoptotic injury develops selectively in immature neurons. We proposed that the GABA(A) receptors (GABA(A)Rs)-mediated excitatory synaptic signaling due to high expression of the Na+-K+-2Cl(-) co-transporter (NKCC1), occurring during the early neuronal development period, plays a distinct role in the susceptibility of immature neurons to ketamine-induced injury. Using whole-cell patch-clamp recordings from the forebrain slices containing the anterior cingulate cortex, we found that in vivo repeated ketamine administration significantly induced neuronal hyperexcitability in neonatal, but not adolescent, rats. Such hyperexcitability was accompanied by the increase both in GABA(A)R- and NMDAR-mediated synaptic transmissions. An interference with the NKCC1 by bumetanide treatment completely reversed these enhanced effects of ketamine exposure and blocked GABA(A)R-mediated postsynaptic current activity. Thus, these findings were significant as they showed, for the first time, that GABA(A)R-mediated excitatory action may contribute distinctly to neuronal excitotoxic effects of ketamine on immature neurons in the developing brain.