Propofol‐induced downregulation of NR2B membrane translocation in hippocampus and spatial memory deficits of neonatal mice

Abstract

BackgroundThousands of infants and children are undergoing anesthesia around the world every day. But impacts of anesthetics on the developing neural system remain unclear yet. Previous evidence showed that anesthesia might affect the developing neural system. Thus, early‐life anesthesia becomes a critical issue in clinical pediatric practice. Hence, propofol, a short‐acting and widely applied intravenous anesthetic, has been gaining focus upon neonatal anesthesia.MethodsFifty‐four male C57BL/6J mice were randomly divided into following three groups: group D6 intraperitoneally (i.p.) injected propofol (100 mg/kg body weight) once a day from postnatal day 6 (P6) to P11, group D1 administrated propofol (100 mg/kg, i.p.) at P6 solely and administrated normal saline (10 ml/kg, i.p.) from P7 to P11, and group N treated with normal saline (10 ml/kg, i.p.) from P6 to P11 as the control (n = 18 per group). Then, at P28, nine mice were collected randomly from each group for NR2B membrane translocation and phosphorylation analysis, and the rest half in each group were assigned to perform Morris water maze tests from P28 to P35.ResultsResults showed that total protein expression levels of NR2B increased (p < .001) while its membrane translocation decreased (p < .001, n = 9 per group) in the hippocampus but not in the prefrontal cortex of neonatal mice after repeated propofol administration. Phosphorylation levels of NR2B at serine 1303 (D1: p < .05; D6: p < .001, n = 9 per group) and serine 1480 (D1: p < .01, D6: p < .001, n = 9 per group) increased significantly as well in the hippocampus compared with group N. In addition, memory deficits (p < .05, n = 9 per group) were observed in Morris water maze tests of group D6 mice.ConclusionsThese results suggested that propofol exposure downregulates NR2B membrane translocation and causes spatial memory deficits, with a mediated increased NR2B protein expression and phosphorylation at Ser1303/1480 residues in the hippocampus of neonatal mice.

GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1

“…From a molecular perspective, NMDAR are tetrameric structures assembled from two obligatory GluN1 subunits and two GluN2A (formerly NR2A) or GluN2B (formerly NR2B) subunits. Evidence suggests that the NR2B subunit in the hippocampus is particularly important for NMDAR channel function ( Akashi et al, 2009 ), long-term potentiation (LTP), and associated cognitive functions such as spatial learning ( Clayton et al, 2002 ; Wang et al, 2017 ; Xu et al, 2017 ). Accordingly, numerous studies have suggested that NR2B, rather than NR2A, is involved in schizophrenia in humans ( Loftis and Janowsky, 2003 ; Geddes et al, 2014 ) and schizophrenia-like behaviors induced by NMDAR antagonists in rodents ( Jiménez-Sánchez et al, 2014 ).…”

Postconditioning with Sevoflurane or&nbsp;Propofol Alleviate Lipopolysaccharide-Induced Neuroinflammation, but Exert Dissimilar Effects on NR2B Subunit and Cognition

“…For instance, iso urane up-regulated extrasynaptic NR2B in the hippocampus in elderly rats and impaired cognitive function [24]; and iso urane or sevo urane upregulated NR2B in the hippocampus, facilitated LTP in CA1 area, and improved cognition in adult mice [14,16]. Sevo urane induced NR1 and NR2B up-regulation, NR2A down-regulation in the PFC, and caused cognitive de cits in adolescent rats [71], while propofol down-regulated NR1, NR2B, NR2A, and PSD-95 in the PFC of developing rat brain, and caused long-term cognitive dysfunction [17,72]. The possible reasons for this discrepancy might be different ages, species of animals, and strategies of drug treatment.…”

“…The NR1 subunit is an essential part of NMDAR, while the NR2 subunits, especially NR2A and NR2B, are mainly distributed in the adult rat hippocampus, and primarily regulate the function of the receptor [13]. Previous studies suggested that inhalation and intravenous anesthetics exhibited a differential effect on the expression of the NR2B subunit, which was accompanied by changes in cognitive function [14][15][16][17]. For example, iso urane or sevo urane exposure alone could improve cognitive function via an upregulation of NR2B subunit in the hippocampus [14,16], while propofol exposure decreased the level of NR2B subunit in the hippocampus and induced spatial memory de cits, suggesting that upregulation of NR2B exerts the neuroprotective effect [17].…”

“…Previous studies suggested that inhalation and intravenous anesthetics exhibited a differential effect on the expression of the NR2B subunit, which was accompanied by changes in cognitive function [14][15][16][17]. For example, iso urane or sevo urane exposure alone could improve cognitive function via an upregulation of NR2B subunit in the hippocampus [14,16], while propofol exposure decreased the level of NR2B subunit in the hippocampus and induced spatial memory de cits, suggesting that upregulation of NR2B exerts the neuroprotective effect [17]. However, overexpression of the NR2B subunit is deleterious in many neurodegenerative disease models [18][19][20].…”

Saline as a vehicle control does not alter ventilation in male CD-1 mice

“…; Wang et al. ). A volume of 10 mL/kg is considered the highest recommended amount for i.p., and this dose was chosen to elicit a maximal response.…”