Ketamine prevents ECS-induced synaptic enhancement in rat hippocampus

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Neuroscience Letters 178 (1994) 11-14

NEURDSCHiC[ LETTERS

Ketamine prevents ECS-induced synaptic enhancement in rat hippocampus Caroline A. Stewart*, Ian C. Reid Department of Mental Health, Universityof Aberdeen, Polwarth Building, Foresterhill, Aberdeen, UK

Received 5 May 1994;Revisedversion received4 July 1994;Accepted4 July 1994

Abstract

Electrical induction of seizure activity profoundly impairs hippoeampal long-term potentiation (LTP) in rats. A similar effect may account for the memory dysfunction observed after electroconvulsivestimulation in humans and other species. The co-administration of ketamine with the induction of electroconvulsive seizures (ECS) was evaluated as a possible method for reducing the impact of ECS on hippocampal synaptic plasticity in rats. Electrophysiologiealstudies in vivo showed that both the enhancement of the EPSP slope and the subsequent reduction of experimentally induced LTP in the dentate gyrus by repeated, spaced ECS were significantly attenuated by ketamine anaesthesia. The findings suggest that ketamine may protect against ECS-inducedmemory impairment and thus prove useful in reducing the transient cognitive impairment following eleetroconvulsivetherapy (ECT). Key words: Long-term potentiation; Electroconvulsive stimulation; Dentate gyrus; NMDA receptor; Depression; Memory

Electroconvulsive stimulation (ECS) has long been known to induce memory deficits in a variety of species. This effect is not without clinical significance - disruption of memory function is a frequent and unpleasant side effect of electroconvulsive therapy (ECT), an otherwise safe and effective treatment for severe depressive disorder in humans. Many attempts have been made to attenuate the effects of ECT on memory using pharmacological methods with limited success [8]. A principal obstruction in this regard has been ignorance of the neurobiological basis of the amnesia which follows ECT. Recent studies have shown that repeated ECS profoundly disrupts a form of synaptic plasticity known as long-term potentiation (LTP) in the rodent hippocampus in vivo [15] and in hippocampal slices studied in vitro following ECS administered to whole animals in vivo [1]. Hippocampal slice preparations subjected to seizure-like stimuli also show disrupted LTP induction [11]. Given that hippocampal LTP is implicated in memory forma-

*Correspondingauthor. Departmentof BiomedicalSciences, Universityof Aberdeen, MarischalCollege,Broad Street, Aberdeen AB9 1AS,UK. Fax:(44) 224-273019. E-mail:[email protected]. 0304-3940/94/$7.00 © 1994 ElsevierScienceIreland Ltd. All rights reserved SSDI 0304-3940(94)00522-2

tion [12, 13], it has been proposed that ECS-induced memory impairment is mediated by interference with the LTP process [1,15]. LTP was first demonstrated in the dentate gyrus of the anaesthetised rabbit [3]. Induction of LTP is dependent on the special characteristics of the N-methyl-D-asparate (NMDA) receptor [5]. Pharmacological blockade of the NMDA receptor using the reversible NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (o-AP5) both inhibits LTP induction and disrupts spatial learning in the open field watermaze in rats in a correlated, dose-dependent manner [6]. Repeated ECS also disrupts acquisition of this task in rats [2,161. Pharmacological modulation of the LTP process may protect hippocampal plasticity from ECS-induced dysfunction and thus reduce the ensuing cognitive impairment observed behaviourally. The precise mechanism by which ECS alters the characteristics of hippocampal LTP is not yet fully established. Electrophysiological recording following a course of repeated spaced ECS in rats shows that, in the dentate gyrus at least, the EPSP slope is significantly elevated in concert with a long lasting (up to 40 days) reduction in the degree to which LTP can be induced experimentally. The effect on EPSP slope

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C A . Stewart, I.C. Reid/Neuroscience Letters 178 (1994) 11 14

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Fig. I. A: the effect of sham (open circles) or ECS (filled triangles) treatments under halothane anaesthesia on LTP induction in the dentate gyrus. B: the effect of sham (open squares) or ECS (filled, inverted triangles) treatments under ketamine anaesthesia on LTP induction. C: representative synaptic responses from sham and ECS groups under halothane anaesthesia pre-tetanus (solid line) and post-tetanus (broken line). D: representative synaptic responses from sham and ECS groups under ketamine anaesthesia pre-tetanus (solid line) and post-tetanus (broken line). Calibration bar, 5 mV, 5 ms. Note that while ECS has a profound effect on LTP induction under halothane anaesthesia, this effect is prevented under ketamine anaesthesia. develops gradually and cumulatively during a course of repeated ECS [14]. We have interpreted these observations as indicating that LTP-like synaptic efficacy changes are incrementally induced during repeated ECS and propose that ECS tends to 'saturate' hippocampal synaptic plasticity such that the capacity for change is reduced. If this hypothesis is correct, it should be possible to reduce the effect of ECS on synaptic plasticity by blocking N M D A receptors during electroconvulsive stimulation. Ketamine is a non-competitive antagonist of the N M D A receptor complex [10] which is clinically available as a dissociative anaesthetic. It has been shown to block LTP induction in vivo [17]. We therefore examined the effect of the co-administration of ECS and ketamine on synaptic plasticity. Male hooded lister rats were assigned to each of four groups. Two of the groups received a course of 10 repeated, spaced ECS (200 V, 50 m A for 2 s trans-cranially) once every 48 h under either inhalational halothane anaesthesia (n---9) or intraperitoneally administered ketamine (Vetalar 10 mg/kg) anaesthesia (n = 10). Seizure length was timed using a stopwatch. The remaining two groups received repeated halothane (n = 10) or ketamine (n = 9) anaesthesia and equivalent handling with-

out the application of current (sham treatments). Animals receiving halothane anaesthesia were also given equivalent volumes of physiological saline (i.p.) to control for the effects of injection. Electrophysiological measures were conducted 24 h after the last seizure or sham treatment. Field potentials generated by perforant path stimulation were recorded from the hilus of the dentate gyrus under urethane anaesthesia (1.5 g/kg). The animals were placed in a K o p f stereotaxic frame and a teflon coated stainless steel bipolar stimulating electrode was lowered into the perforant path (AP = 7.5 ram, M L = 4.1 m m relative to Bregma) to a depth of 2.0-2.5 m m from the brain surface. The recording electrode was lowered toward the dentate hilus (AP = 3.8, M L = 2.2) in steps of 0.2 m m until the maxim u m response was obtained, usually at a depth of 2.53.0 mm. Low frequency stimulation (0.05 Hz, 0.1 ms, 700 /IA) was delivered using a stimulus isolator controlled by computer (Acorn RISC-OS) until measurements of the EPSP slope and population spike height were stable. A 15 minute baseline was run using the same low frequency protocol and then a high frequency tetanus was delivered (4 trains of 33 pulses at 400 Hz with 20 s inter-train intervals). The response was monitored at low frequency

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C.A. Stewart, I.C. Reid/Neuroscience Letters 178 (1994) 11-14

for a further 60 minutes. The field potentials were amplified (Grass Instruments) then sampled by computer (10,000 Hz for 20 ms) using an analogue to digital converter board (Wild Vision). The early rising EPSP slope (mV/ms) of the waveform was recorded and analysed and the percentage change following high frequency stimulation (LTP) was calculated for each subject by comparing the mean value derived from the 10 samples measured 60 minutes after tetanus with the baseline mean derived from the last 10 samples before tetanus. The amount of LTP induced in each group expressed as the percentage increase in EPSP slope above baseline is shown in Fig. 1. Statistical analysis (ANOVA) indicated that the amount of LTP measured 60 min post induction (Fig. 2A) differed significantly among the groups (F3,34--8.26, P < 0.0005), and post-hoc testing (Neuman-Keuls pair-wise comparisons, P < 0.05) revealed that significantly less LTP was induced in the group given halothane during ECS (6.4% + 2.0 S.E.M.) when compared to the group given ECS under ketamine anaesthesia (20.2% + 3.1 S.E.M.) and the two sham groups (halothane = 31.8% + 4.8 S.E.M.; ketamine = 25.0% + 4.2 S.E.M.). The effects of the various treatments on EPSP slope function observed at low frequency prior to LTP induction are shown in Fig. 2B (Sham halothane = 3.24 mV/ms + 0.2 S.E.M.; ECS halothane = 4.57 mV/ms + 0.4 S.E.M.; Sham ketamine = 3.2 mV/ ms + 0.2 S.E.M.; ECS ketamine = 2.7 mV/ms + 0.1 S.E.M.). Analysis of variance indicated that there was a significant effect of Group (F3,34--11.1, P < 0.0001), with the group receiving ECS under halothane anaesthesia showing a significantly greater EPSP slope (NeumanKeuls, P < 0.05) than all other groups (which did not differ one from another). Seizure length recorded across the series of treatments was slightly but significantly reduced in the group receiving ketamine anaesthesia (mean under halothane = 18.4 s + 0.3 S.E.M.; mean under ketamine = 13.9 s _+ 0.4 S.E.M.; FI,I7 = 33.0, P < 0.0001) In each group seizure length remained consistent across treatments. The previously reported elevation of EPSP initial slope and subsequent reduction of LTP induction following repeated spaced ECS under halothane anaesthesia [15] was confirmed. As predicted, the concurrent administration of ketamine with ECS prevented this effect, such that elevation of slope function was not observed and LTP induction preserved. It was noted that seizure length was reduced by ketamine anaesthesia and this anticonvulsant effect may be a reflection of N M D A blockade during seizure induction. The anticonvulsant effects of ketamine and other phencyclidine-like drugs are well known and it has been shown that the protection given by these compounds from maximal electric shockinduced tonic-extensor seizures correlates with the minimal effective dose required to block NMDA-induced lethality [9]. It is likely that there is a complex and inti-

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Fig. 2. A: effectof sham or ECS treatments under halothane or ketamine anaesthesia at 60 min post-tetanus (mean of last 10 values divided by last 10 baseline values + S.E.M.) B: effectof ECS or sham treatment on EPSP slope under halothane or ketamine anaesthesia prior to LTP induction (mean of last 10 baseline EPSP slope values + S.E.M.).Open bars = halothane anaesthesia, shaded bars = ketamine anaesthesia. Note that the reducedLTP in the ECS group givenhalothane anaesthesia is associated with a higher initial EPSP slope.

mate relationship between seizure induction and spread, N M D A receptor activation and hippocampal synaptic efficacy changes. It remains to be determined whether the effect of ketamine on ECS-induced synaptic changes in the rat offers a specific neuroprotective effect through blockade of the N M D A receptor, rather than some other unrelated anaesthetic effect, and whether ketamine administration also reduces the cognitive consequences of ECS administration. Clinical studies may help resolve this issue. From a clinical perspective, an ideal agent would reduce cognitive impairment without interfering with the antidepressant efficacy of ECT. Ketamine has been evaluated for use in electroconvulsive therapy and found to be safe and effective from the point of view of the anaesthetist [4,7], but ketamine is rarely used and no assessment has been made of impact on either antidepressant efficacy or cognitive dysfunction. Interestingly, the related N M D A receptor channel blocker dizocilpine (MK801) has been shown to have antidepressant activity in preclinical animal models of depressive disorder [18], and it is therefore conceivable that ketamine possesses similar antidepressant activity in addition to the potential for reducing cognitive dysfunction. In light of the findings reported here, we feel that the use of ketamine in electroconvulsive therapy deserves further clinical evaluation. More generally, the model described here could be used to examine other candidate 'memory protectants' and has the advantage over purely in vitro models [11] that plasticity changes can be examined after a longer time interval and corresponding behavioural studies can be carried out. This research was supported by the Royal College of Physicians of Edinburgh (Sim Bequest). Software for sampling evoked potentials was written by Roger Spooner.

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C.A. Stewart, I.C. ReidlNeuroscience Letters 178 (1994) 11-14

[1] Anwyl, R., Walshe, J. and Rowan, M., Electroconvulsive treatment reduces long-term potentiation in rat hippocampus, Brain Res., 435 (1987) 377-379. [2] Barnes, C.A., McNaughton, B.L., Andreasson, K., Church, L. and Worley, P.F., Comparison of LTE-inducing stimulation and electroconvulsive shock on the rostral-caudal extent of hippocampal zif268 mRNA activation, synaptic enhancement and spatial memory disruption, Soc. Neurosci. Abstr., 19 (1993) 794. [3] Bliss, T.V.P. and Lomo, T., Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetised rabbit following stimulation of the perforant path, J. Physiol., 232 (1973) 331356. [4] Brewer, C.L., Davidson, J.R. and Hereward, S., Ketamine ('Ketalar'): a safer anaesthetic for ECT, Br. J. Psychiat., 120 (1972) 679-80. [5] Collingridge, G.L., Kehl, S.J. and McLennan, H., Excitatory amino acids in synaptic transmission in the schaffer collateralcommissural pathway of the rat hippocampus, J. Physiol., 334 (1983) 33-46. [6] Davis, S., Butcher, S.P. and Morris, R.G.M., The NMDA receptor antagonist D-2-amino-5-phosponopentanoate(D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro, J. Neurosci., 12 (1992) 21-34. [7] Green, C.D., Ketamine as an anaesthetic for ECT, Br. J. Psychiat., 122 (1973) 123-124. [8] Krueger, R.B., Sackeim, H.A. and Gamzu, E.R., Pharmacological treatment of the cognitive side effects of ECT: A review, Psychopharmacol. Bull., 28 (1992) 409-424.

[9] Leander, J.D., Rathbun, R.C. and Zimmerman, D.M., Anticonvulsant effects of phencyclidine-like drugs: relation to N-methyl-Daspartic acid antagonism, Brain Res., 454 (1988) 368-372. [10] MacDonald, J.F., Miljkovic, Z. and Pennefather, P., Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine, J. Neurophysiol., 58 (1987) 251-266. [11] Moore, S.D., Barr D.S. and Wilson W.A., Seizure-like activity disrupts LTP in vitro, Neurosci. Lett., 163 (1993) 117-119. [12] Morris, R.G.M., Anderson, E., Lynch, G.S. and Baudry, M., Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonists, AP5, Nature, 319 (1986) 774-776. [13] Silva, A.J., Stevens, C.F., Tonegawa, S. and Wang, Y., Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant, Science, 257 (1992) 206-211. [14] Stewart, C., Jeffery, K. and Reid, I., LTP-like synaptic efficacy changes following electroconvulsive stimulation, NeuroReport, 5 (1994) 1041-1044. [i 5] Stewart, C. and Reid, I.C., Electroconvulsive stimulation and synaptic plasticity in the rat, Brain Res., 620 (1993) 139-141. [16] Stewart, C.A. and Reid, I.C., Repeated electroconvulsive stimulation impairs acquisition of the watermaze task, Brain Res. Assoc. Abstr., 10 (1993) 48. [17] Stringer, J.L. and Guyenet, P.G., Elimination of long-term potentiation in the hippocampus by phencyclidine and ketamine, Brain Res., 258 (1983) 159-164. [18] Trullas, R. and Skolnick, P., Functional antagonists at the NMDA receptor complex exhibit antidepressant actions, Eur. J. Pharmacol., 185 (1990) 1-10.