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

Abstract

Ketamine, a dissociative anesthetic most commonly used in many pediatric procedures, has been reported in many animal studies to cause widespread neuroapoptosis in the neonatal brain after exposure in high doses and/or for prolonged period. This neurodegenerative change occurs most severely in the forebrain including the anterior cingulated cortex (ACC) that is an important brain structure for mediating a variety of cognitive functions. However, it is still unknown whether such apoptotic neurodegeneration early in life would subsequently impair the synaptic plasticity of the ACC later in life. In this study, we performed whole-cell patch-clamp recordings from the ACC brain slices of young adult rats to examine any alterations in long-term synaptic plasticity caused by neonatal ketamine exposure. Ketamine was administered at postnatal day 4–7 (subcutaneous injections, 20 mg/kg given six times, once every 2 h). At 3–4 weeks of age, long-term potentiation (LTP) was induced and recorded by monitoring excitatory postsynaptic currents from ACC slices. We found that the induction of LTP in the ACC was significantly reduced when compared to the control group. The LTP impairment was accompanied by an increase in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated excitatory synaptic transmission and a decrease in GABA inhibitory synaptic transmission in neurons of the ACC. Thus, our present findings show that neonatal ketamine exposure causes a significant LTP impairment in the ACC. We suggest that the imbalanced synaptic transmission is likely to contribute to ketamine-induced LTP impairment in the ACC.

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

“…Ketamine hydrochloride, known simply as ketamine, a non-competitive N- methyl- D -aspartate receptor (NMDAR) antagonist, is commonly used as a pediatric anesthetic. However, multiple animal studies have conclusively shown that prolonged neonatal exposure to ketamine, or its congener, caused widespread neuroapoptosis that ultimately manifested in deficits of learning and memory and impairments in long-term synaptic plasticity in adulthood (Huang, Liu, Jin, Ji, & Dong, 2012; Jevtovic-Todorovic et al, 2003; Wang et al, 2014; Womack et al, 2013). A compensatory upregulation of the NMDARs develops significantly when ketamine is withdrawn, which triggers neuronal excitotoxicity leading to neuroapoptosis (Kokane & Lin, 2016; Slikker et al, 2007; Zou et al, 2009).…”

A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research

“…One study showed evidence of neurotoxicity of sevoflurane at an earlier stage—PD6—associated with caspase activation, apoptosis, and increased levels of beta‐amyloid proteins , and a similar study showed that neonatal ketamine results in long‐term effects .…”

Synaptic Homeostasis and Allostasis in the Dentate Gyrus Caused by Inflammatory and Neuropathic Pain Conditions

“…Spike discharge was recorded at the current clamp mode and postsynaptic currents were recorded at the voltage-clamp mode. Detailed methodology has been described in our previous reports (Gong et al, 2010 ; Wang et al, 2014 ).…”

“…Bicuculline (10 μM), CNQX (10 μM), D-APV (50 μM) and TTX (1 μM) were dissolved in the ACSF to their final concentration on the day of the experiment and applied to the brain slices with perfusion when tested. Selectivity and target concentrations were chosen based on preliminary experiments and previous reports (Gong et al, 2010 ; Wang et al, 2014 ).…”