The blockade of NMDA receptor ion channels by ketamine is enhanced in developing rat cortical neurons

Abstract

Ketamine is a non-competitive antagonist of NMDA receptors (NMDARs) commonly used as a dissociative anesthetic in many pediatric procedures. Ketamine acts primarily by blocking NMDA ligand-gated channels. Experimental studies indicate that ketamine administration used for inducing clinically relevant anesthesia can lead to neurotoxic effects, such as apoptosis, selectively on immature brain neurons. However, the underlying mechanisms remain unclear. This study used whole-cell patch-clamp recordings in an in vitro preparation of forebrain slices to analyze pharmacologically the differences in the effects of ketamine administration on the NMDAR channel activity between immature and mature neurons. NMDAR channel activity was recorded in the form of evoked NMDAR-mediated excitatory postsynaptic currents (eEPSCs) from the forebrain of both neonatal and adult rats. Results show that ketamine inhibited eEPSCs in a dose-dependent manner in both immature and mature neurons. However, at each concentration of ketamine applied to the brain slice, a more extensive inhibition could be seen in neonatal neurons than in adult neurons. Further, the blocking effect of ketamine on eEPSCs was measured during the period of 1, 3, and 6 h after ketamine washout. Inhibition of eEPSCs in immature neurons was still evident 6 h after washout. In contrast, the blockade of eEPSCs in mature neurons recovered completely from the inhibition by ketamine in a time-dependent manner. These results indicate that ketamine produces a greater and longer blocking effect on NMDAR channels in immature neurons than in mature neurons. This differential effect is likely to be a critical link to the higher vulnerability to ketamine-induced neurotoxicity in neurons of the developing brain.

Experimental and clinical evidence of differential effects of magnesium sulfate on neuroprotection and angiogenesis in the fetal brain

“…These differential effects of MgSO 4 and MK801 or ketamine on apoptosis could be explained by specific pharmacological properties. On depolarization, the Mg 2+ block of all NMDA receptor subtypes is relieved (Huang and Gibb 2014); in contrast, the blocking effect of ketamine and MK801 on the NMDA receptor is much longer (Jin et al 2013).…”

“…On depolarization, the Mg 2+ block of all NMDA receptor subtypes is relieved (Huang and Gibb ); in contrast, the blocking effect of ketamine and MK801 on the NMDA receptor is much longer (Jin et al. ).…”

Neonatal ketamine exposure causes impairment of long-term synaptic plasticity in the anterior cingulate cortex of rats

“…and ACC slices were obtained according to previously-published procedures (He et al, 2009; Gong et al, 2010; Jin et al, 2013; Lu et al, 2013). Briefly, after decapitation, the whole brain was carefully removed and quickly transferred to an ice-cold bath of artificial cerebrospinal fluid (ACSF; composition in mM: NaCl 124, KCl 3.3, KH 2 PO 4 1.2, CaCl 2 2H 2 O 2.5, MgSO 4 2.4, NaHCO 3 26, and glucose 10).…”

“…A single brain slice was then held down in the recording chamber with an anchor and was kept immersed in circulating oxygenated ACSF at a flow rate of 2.2–2.6 ml/min using a fast perfusion system (World Precision Instruments, USA). Recordings were done at room temperature (23–25 °C)(Zhao et al, 2005a,2009; He et al, 2009; Gong et al, 2010; Jin et al, 2013). …”

“…Recording procedures, data acquisition and equipment have been described in previously published work by our and other groups (Zhao et al, 2009; Gong et al, 2010; Jin et al, 2013). Briefly, postsynaptic currents were recorded from layers II-III of pyramidal neurons of the ACC because layers II-III are reported to be the major location of intracortical horizontal pathways (Hess et al, 1994), and the superficial layers of the ACC received nucleus of somatosensory information (Zhuo, 2007).…”