Propofol prevents electroconvulsive-shock-induced memory impairment through regulation of hippocampal synaptic plasticity in a rat model of depression

Abstract

Background: Although a rapid and efficient psychiatric treatment, electroconvulsive therapy (ECT) induces memory impairment. Modified ECT requires anesthesia for safety purposes. Although traditionally found to exert amnesic effects in general anesthesia, which is an inherent part of modified ECT, some anesthetics have been found to protect against ECT-induced cognitive impairment. However, the mechanisms remain unclear. We investigated the effects of propofol (2,6-diisopropylphenol) on memory in depressed rats undergoing electroconvulsive shock (ECS), the analog of ECT in animals, under anesthesia as well as its mechanisms.

Methods: Chronic unpredictable mild stresses were adopted to reproduce depression in a rodent model. Rats underwent ECS (or sham ECS) with anesthesia with propofol or normal saline. Behavior was assessed in sucrose preference, open field and Morris water maze tests. Hippocampal long-term potentiation (LTP) was measured using electrophysiological techniques. PSD-95, CREB, and p-CREB protein expression was assayed with Western blotting.

Results: Depression induced memory damage, and downregulated LTP, PSD-95, CREB, and p-CREB; these effects were exacerbated in depressed rats by ECS; propofol did not reverse the depression-induced changes, but when administered in modified ECS, propofol improved memory and reversed the downregulation of LTP and the proteins.

Conclusion: These findings suggest that propofol prevents ECS-induced memory impairment, and modified ECS under anesthesia with propofol improves memory in depressed rats, possibly by reversing the excessive changes in hippocampal synaptic plasticity. These observations provide a novel insight into potential targets for optimizing the clinical use of ECT for psychiatric disorders.

Keywords: CREB; PSD-95; electroconvulsive therapy; long-term potentiation.

Figure 1

Experimental timeline of this study. Notes: Sham CUMS, without any treatment (for group C); Sham ECS (for group D), Sham MECS (for group P). Abbreviations: CUMS, chronic unpredictable mild stresses (for groups D, P, E, and M); ECS, electroconvulsive shock (for group E); MECS, modified ECS (for group M); MWM, Morris water maze test; OFT, open field test; SPT, sucrose preference test; ×, sacrifice.

Figure 2

Sucrose preference in rats after ECS (or MECS) treatment. Notes: Data are presented as the mean ± SE; **P<0.01 and ***P<0.001 versus group C; ^###P<0.001 versus group D; P<0.001 versus group P. C represents control rats; D represents CUMS-pretreated rats that received sham ECS with normal saline pretreatment; P represents CUMS-pretreated rats that received sham ECS with propofol pretreatment; E represents CUMS-pretreated rats that received ECS with normal saline pretreatment; M represents CUMS-pretreated rats that received ECS with propofol pretreatment; n=10 in each group. Abbreviations: CUMS, chronic unpredictable mild stresses; ECS, electroconvulsive shock; MECS, modified ECS; SE, standard error.

Figure 3

Indexes in open field test in rats after ECS (or MECS) treatment. Notes: Distance (A); rearing number (B); time in the central zone (C). Data are presented as the mean ± SE. **P<0.01 and ***P<0.001 versus group C; ^###P<0.001 versus group D; P<0.001 versus group P. C represents control rats; D represents CUMS-pretreated rats that received sham ECS with normal saline pretreatment; P represents CUMS-pretreated rats that received sham ECS with propofol pretreatment; E represents CUMS-pretreated rats that received ECS with normal saline pretreatment; M represents CUMS-pretreated rats that received ECS with propofol pretreatment; n=10 in each group. Abbreviations: CUMS, chronic unpredictable mild stresses; ECS, electroconvulsive shock; MECS, modified ECS; s, seconds; SE, standard error.

Figure 4

Learning and memory in Morris water maze test in rats after ECS (or MECS) treatment. Notes: Evasive latency (A); division of different quarters in the test (B); time percentage in the platform quarter of each group (C); time percentage in each quarter in group C (D); time percentage in each quarter in group D (E); time percentage in each quarter in group P (F); time percentage in each quarter in group E (G); time percentage in each quarter in group M (H). Data are presented as the mean ± standard error; **P<0.01, ***P<0.001 versus group C or quarter NW; ^#P<0.05, ^##P<0.01, and ^###P<0.001 versus group D or quarter NE; P<0.05, P<0.01, and P<0.001 versus group P or quarter SW; ^ΔΔP<0.01, ^ΔΔΔP<0.001 versus group E. C represents control rats; D represents CUMS-pretreated rats that received sham ECS with normal saline pretreatment; P represents CUMS-pretreated rats that received sham ECS with propofol pretreatment; E represents CUMS-pretreated rats that received ECS with normal saline pretreatment; M represents CUMS-pretreated rats that received ECS with propofol pretreatment. • Represents platform; n=10 in each group. Abbreviations: CUMS, chronic unpredictable mild stresses; ECS, electroconvulsive shock; MECS, modified ECS; NE, northeastern quarter; NW, northwestern quarter; SE, southeastern quarter; SW, southwestern quarter (ie, the platform quarter).

Figure 5

LTP in the CA1 region in hippocampus of rats after ECS (or MECS) treatment. Notes: Original traces of fEPSP in each group (A); input/output curves in each group (B); the induction and maintenance of LTP (C); baseline fEPSP slope (D); relative fEPSP slope (E). Data are presented as the mean ± SE; *P<0.05, ***P<0.001 versus group C; ^#P<0.05, ^###P<0.001 versus group D; P<0.05, P<0.001 versus group P; ^ΔΔΔP<0.001 versus group E. C represents control rats; D represents CUMS-pretreated rats that received sham ECS with normal saline pretreatment; P represents CUMS-pretreated rats that received sham ECS with propofol pretreatment; E represents CUMS-pretreated rats that received ECS with normal saline pretreatment; M represents CUMS-pretreated rats that received ECS with propofol pretreatment; n=5 in each group. ^aoriginal trace of baseline fEPSP; ^boriginal trace of fEPSP after HFS. Abbreviations: CUMS, chronic unpredictable mild stresses; ECS, electroconvulsive shock; fEPSP, field excitatory postsynaptic potential; HFS, high frequency stimulation; LTP, long-term potentiation; MECS, modified ECS; SE, standard error.

Figure 6

Hippocampal PSD-95 protein expression in rats after ECS (or MECS) treatment. Notes: Western blot bands of PSD-95 and β-actin (A); relative expression of PSD-95 protein (B). Data are presented as the mean ± SE; ***P<0.001 versus group C; ^#P<0.05 versus group D; P<0.05 versus group P; ^ΔΔP<0.01 versus group E. C represents control rats; D represents CUMS-pretreated rats that received sham ECS with normal saline pretreatment; P represents CUMS-pretreated rats that received sham ECS with propofol pretreatment; E represents CUMS-pretreated rats that received ECS with normal saline pretreatment; M represents CUMS-pretreated rats that received ECS with propofol pretreatment; n=6 in each group. Abbreviations: CUMS, chronic unpredictable mild stresses; ECS, electroconvulsive shock; MECS, modified ECS; PSD-95, postsynaptic density-95; SE, standard error.

Figure 7

Hippocampal CREB/p-CREB protein expression in rats after ECS (or MECS) treatment. Notes: Western blot bands of CREB/p-CREB and β-actin (A); relative expression of CREB protein (B); relative expression of p-CREB protein (C). Data are presented as the mean ± SE; **P<0.01, ***P<0.001 versus group C; ^#P<0.05, ^##P<0.01 versus group D; P<0.05, P<0.01 versus group P; ^ΔΔΔP<0.001 versus group E. C represents control rats; D represents CUMS-pretreated rats that received sham ECS with normal saline pretreatment; P represents CUMS-pretreated rats that received sham ECS with propofol pretreatment; E represents CUMS-pretreated rats that received ECS with normal saline pretreatment; M represents CUMS-pretreated rats that received ECS with propofol pretreatment; n=5–6 in each group. Abbreviations: CUMS, chronic unpredictable mild stresses; ECS, electroconvulsive shock; MECS, modified ECS; SE, standard error.