~ Pergamon 0306-4522(94)00550-8 Neuroscience Vol. 65, No. 3, pp. 661-670, 1995 Elsevier ScienceLtd Copyright © 1995 IBRO Printed in Great Britain. All rights reserved 0306-4522/95 $9.50 + 0.00 SPATIOTEMPORAL SELECTIVE EFFECTS ON BRAIN-DERIVED NEUROTROPHIC FACTOR AND trkB MESSENGER RNA IN RAT HIPPOCAMPUS BY ELECTROCONVULSIVE SHOCK N. LINDEFORS,*t E. BRODIN:~ and M. METSIS§ tDepartment of Clinical Neuroscience, Section for Psychiatry and Psychology, ~:Department of Physiology and Pharmacology, and §Department of Medical Biochemistry and Biophysics, Laboratory for Molecular Neurobiology, Karolinska Institutet, P.O. S-171 76 Stockholm, Sweden Abstract--Electroconvulsive therapy is used in the treatment of affective disorders and schizophrenia and experimental electroconvulsive shock may serve as an animal model for this treatment. The aim of this study was to investigate a possible role for neurotrophins in the mechanism of action of experimental electroconvulsive shock and thus in clinical electroconvulsive therapy. The effect of electroconvulsive shock on levels of messenger RNAs encoding the neurotrophin brain-derived neurotrophic factor and the receptor trkB in rat hippocampus was determined by in situ hybridization with RNA probes 1, 3, 9 and 27 h following the shock. Brain-derived neurotrophic factor messenger RNA levels were increased at l, 3 and 9 h following the shock and normalized after 27 h. Granule cells of the dentate gyrus showed a more rapid response as compared to hilar cells and pyramidal cells of CA1. Total trk B messenger RNA levels, including the transcripts for both the truncated and full length trk B receptor protein (gp9Y rkB and gpl45 trkB, respectively), showed a pattern of increase very similar to that of the brain-derived neurotrophic factor messenger RNA. However, using a probe selective for the full length (gpl4Y rkB) trkB messenger RNA, we determined a delayed pattern of activation with significant increase only at 3 and 9 h after the shock. In hippocampus total trkB messenger RNA was found to consist of approximately one-quarter of mRNA encoding gpl45 trkB and three-quarters encoding gp95/rkB as revealed by RNAase protection. While brain-derived neurotrophic factor and the truncated trkB messenger RNAs appear to increase with a similar pattern, suggesting a similar mechanism of activation by electroconvulsive shock, full length receptor trk B messenger RNA appears to increase with a delayed pattern suggesting a separate mechanism of activation. Electroconvulsive shock-induced seizures seem to include activation of a brain neurotrophin known to be important for neuronal plasticity. Electroconvulsive therapy (ECT) is used in the treat- ment of severe depression and in some cases is also an effective antipsychotic agent. 47 In treatment of schizophrenia, ECT is particularly efficient in the case of catatonic or affective presentation. The develop- ment of efficient neuroleptic drugs has put ECT in a secondary position in schizophrenia treatment. Never- theless, recent data indicate that ECT may be ben- eficial given together with neuroleptics in treatment of treatment-resistant schizophrenia. 4z The mechan- ism of action of ECT in treatment of depression and schizophrenia remains obscure. Experimental electro- convulsive shock (ECS) is often used as an animal model for ECT. Using a similar shock paradigm as in clinical ECT, experimental ECS can affect both neurotransmitter receptors and neuropeptides and transmitter synthesizing enzymes at the protein or *To whom correspondence should be addressed. Abbreviations: BDNF, brain-derived neurotrophic factor; CA, cornu ammonis, i.e. Ammons horn of hippo- campus; ECS, electroconvulsive shock; ECT, electrocon- vulsive therapy; EDTA, ethylenediaminetetra-acetate; SSC, saline-sodium citrate buffer. mRNA level. 9'1°'18'31'32 Transcription factor mRNAs for zif/268, c-fos, c-jun and jun-B have been reported to increase transiently following ECS, in particular in the hippocampus) 1 In successful clinical use, short ECT series of approximately five to l0 repeated treatment shocks produce a long-lasting attenuation of disease symptoms when appropriate indications are fulfilled. 47 This suggests that ECT induces a stable change in neuronal function in regions of the brain involved in the pathophysiology of depression or catatonic schizophrenia. The hippocampus is important for cognitive functions such as spatial orientation and memory formation? Experimental kindling epileptogenesis shows that the hippocampal formation is prone to start epileptogenic activity. 17 Since ECS as well as ECT include epileptic convulsions, the hippocampus might be a relevant area to study for their mechan- isms of action. Anatomically, the hippocampus re- ceives major afferent glutamatergic projections from the entorhinal cortex and cholinergic afferents from the septal area. 3 Afferent pathways also include monoaminergic neurons from midbrain dopamin- ergic, serotonergic and noradrenergic cell groups. The Nsc 65/3-B 661