br Experimental procedures br Results br Discussion

Experimental procedures
Results
Discussion
Acknowledgments SRE and EBL contributed equally to this acetylcholinesterase inhibitor work. SRE, EBL, and MJT designed experiments, SRE, EBL, MCH, and AEI conducted experiments, SRE and EBL analyzed data, and EBL and MJT wrote the manuscript. We would like to thank Dr. Manuel Esguerra and Dr. Michael Benneyworth for insightful comments and discussion related to this manuscript and Keelia Silvis, Ethan Huffington, and Johanna Back for technical assistance. This work was supported by funding from the National Institute on Drug Abuse grants R01 DA019666, R21 DA033457, K02 DA035459 (MJT) and T32 DA007234 (SRE and AEI), and by the University of Minnesota MnDRIVE Foundation (EBL and MCH). Behavioral experiments were run in the University of Minnesota Mouse Behavioral Core (supported by National Institutes of Health grant P30NS062158). The authors have no conflicts of interest related to this work.
Introduction Pentobarbital, a barbiturate, has been used as a general anesthetic, to treat insomnia, for sedation and status epilepticus for many years. However, as an anesthetic drug, pentobarbital also has some side effects including amnesia, one of the important causes of postoperative cognitive dysfunction. Previous studies have shown that pentobarbital quantitatively impairs the memory acquisition process and is involved in short-term recall performance [1]. The systemic application of pentobarbital can produce memory dissociation in rats [2] and disrupt short-term memory and attention in monkeys when performing an operant behavioral test battery [3]. A recent study has reported that neonatal administration with pentobarbital leads to spatial memory impairment that can persist into adulthood [4]. We have previously shown that acute hippocampal microinjection of pentobarbital caused dramatic learning and memory deficits [5]. However, the mechanism of pentobarbital-induced memory deficit remains poorly understood. It is widely accepted that synaptic plasticity in the CA1 area of the hippocampus, measured as long-term potentiation (LTP) and long-term depression (LTD), is the cellular mechanism underlying information processing and memory formation [6], [7], [8]. Evidence accumulated from recent studies suggests that LTD can be induced through a number of cellular processes that are either NMDA-dependent or NMDA-independent [9], [10], with a common final step entailing the endocytosis of postsynaptic AMPARs [11], [12]. Consistent with these findings, we have recently reported that inhibition of AMPAR endocytosis by a synthesized peptide GluA23Y can prevent LTD expression [13], [14], [15] and prolong memory retention [16]. A previous study showed that administration of propofol, another highly effective intravenous anesthetic, produces dose-dependent suppression of LTP and basal synaptic transmission [17]. Similarly, our recent study revealed that pentobarbital suppressed hippocampal LTP and decreased neuronal excitability, which may lead to spatial learning and memory deficits [5]. Therefore, we hypothesized that inhibiting AMPAR endocytosis by GluA23Y may alleviate the pentobarbital-induced synaptic and memory deficits. In the present study, we investigated this hypothesis by using a combination of electrophysiological, behavioral and biochemical assessments.
Materials and methods
Results
Discussion The main findings of the present study are that pentobarbital causes the impairment of spatial memory retrieval and suppresses the basal synaptic transmission. More specifically, inhibiting GluA2-containing AMPAR endocytosis by GluA23Y peptide partially rescues the memory deficits and synaptic depression induced by pentobarbital. This provides evidence that pentobarbital-impaired spatial memory retention may be attributed to AMPAR endocytosis-mediated synaptic depression, and suggests that GluA23Y may be a potential therapeutic drug against pentobarbital-caused memory disorder in the clinic.