Research Report Ketamine pre-treatment dissociates the effects of electroconvulsive stimulation on mossy fibre sprouting and cellular proliferation in the dentate gyrus Steven R. Lamont a , Brendan J. Stanwell a , Rachel Hill a , Ian C. Reid b , Caroline A. Stewart a, * a University of Dundee, Division of Pathology and Neuroscience, Section of Psychiatry and Behavioural Sciences, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK b University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK Accepted 5 June 2005 Available online 20 July 2005 Abstract Electroconvulsive stimulation (ECS), the experimental analogue of electroconvulsive therapy (ECT), has been shown to produce both functional and structural effects in the hippocampal formation in infrahuman species. These changes may relate to the antidepressant and cognitive effects of ECT observed in patients treated for severe depressive disorders. Recent studies have described both enhanced neurogenesis in the dentate gyrus of the hippocampus and sprouting of mossy fibre projections from granule cells. The behavioural significance of these effects remains uncertain. In this study, we examined whether ketamine, a clinically available non-competitive NMDA receptor channel blocker, could block both of these ‘‘trophic’’ effects. Rats were given a course of eight spaced ECS or sham treatments under either halothane or ketamine anaesthesia. The thymidine analogue bromodeoxyuridine was administered to assess the degree of hippocampal cell proliferation and mossy fibre sprouting was quantified using the Timm staining method. Pre-treatment with ketamine dissociated these effects such that mossy fibre sprouting was attenuated significantly, while cell proliferation was unaffected. This dissociation may prove useful in determining the behavioural significance of these hippocampal changes, if any, for either the antidepressant or cognitive consequences of ECT. D 2005 Elsevier B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Neuropsychiatric disorders Keywords: Bromodeoxyuridine; Antidepressant; Hippocampus; NMDA; Cognition 1. Introduction Electroconvulsive therapy (ECT) remains one of the most effective treatments for severe depression [7]. The precise mechanism of action remains unknown. Recent studies in the rats indicate that electroconvulsive stimulation (ECS) causes both structural and functional changes within the hippocampal formation, particularly the dentate gyrus. Although the clinical relevance of these findings has yet to be determined, it has been suggested that they may act to compensate for some of the atrophic changes seen following stress in animals [14] or severe, chronic depression in humans [29]. Repeated ECS causes sprouting of mossy fibres (the major axonal projection from dentate granule cells) into both the supragranular layer of the dentate gyrus [19,35] and the stratum oriens of CA3 [13]. ECS also increases neurogenesis, the production of new neurones from pro- genitor cells, within the dentate gyrus [22,28]. Although both of these effects could be described as ‘‘neurotrophic’’, there is evidence from epilepsy-related research to suggest that they may be dissociable: mossy fibre sprouting may, 0006-8993/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2005.06.041 * Corresponding author. Fax: +44 1382 633923. E-mail address: c.a.stewart@dundee.ac.uk (C.A. Stewart). Brain Research 1053 (2005) 27 – 32 www.elsevier.com/locate/brainres