Pergamon PH: S0197-0186(96)00112,-X Neurochem. Int. Vol. 31, No. 3, pp. 425-436, 1997 © 1997Elsevier Science Ltd Printed in Great Britain.All fightsreserved 0197-0186/97 $17.00+0.00 ON THE ROLE OF c-fos EXPRESSION IN STRIATAL TRANSMISSION. THE ANTISENSE OLIGONUCLEOTIDE APPROACH WOLFGANG SOMMER* and KJELL FUXE Department of Neuroscience, Karolinska Institute, Stockholm 171 77, Sweden (Received 9 February 1996; accepted 30 May 1996) Abstract--The antisense oligonucleotide approach has been established as a tool to analyse the functional role of c-fos gene expression in the striatum. Studies on the distribution and cellular localization of microinjected oligonucleotides, as well as their effect on gene expression, demonstrate that the action of the c-fos oligonucleotides can be used to evaluate the role of c-fos gene expression selectively in neuronal function. Antisense oligonucleotides to c-fos inhibit both basal and stimulated c-fos expression in the striatum, which leads to characteristic changes in behavioural and biochemical parameters, as evaluated by analysis of rotational behaviour and dual probe in vivo microdialysis for the neurotransmitter GABA, respectively. These observations could be explained by a postulated D 1/NMDA receptor interaction in the striatonigral GABA pathway controlled by the immediate early gene c-fos. We concluded that c-fos might be involved not only in the control of long-term changes in the cellular phenotype but also in control of firing rate. © 1997 Elsevier Science Ltd The release of transmitters, such as glutamate, ace- tylcholine and catecholamines in the central nervous system (CNS) often leads to neuronal activation which has been associated with long-term changes in neu- ronal gene expression. Such changes in gene expression are brought about by the ability of specific cell surface receptors for neurotransmitters to induce immediate-early genes through coupling to tran- scriptional activation. One of the best known immedi- ate-early genes is c-fos, which is an established marker for neuronal activation. It only has a low con- centration constitutive expression, and has therefore been considered mainly as a regulator of the expression of genes following neuronal activation, leading to marked increases in its transcription and translation (see Morgan and Curran, 1991). The c- fos gene belongs to a family of related genes which, together with thejun gene family, form arrays of dim- eric phosphoprotein complexes binding to the acti- vator protein-1 (AP-1) response element site, which is situated in the promoter regions of a vast number of genes. A currently held view is that activation of the c-fos gene results in metabolic changes such as the *To whom all correspondence should be addressed. Tel.: +46 (8) 728 7080; Fax: +46 (8) 33 79 41; E-mail: wolfgang.sommer@neuro.ki.se. synthesis of neuropeptides or factors involved in cell growth or cell cycle regulation, differentiation and apoptosis. In this way, long-term changes in the cellu- lar phenotype and in functions such as adaptation, addiction, tolerance, memory, degeneration and regeneration can be obtained (for review see Hughes and Dragunow, 1995). It is presently unknown to what extent the Fos protein can be involved in the regulation of transmission including the firing rate in central neurons, and thus in inducing behavioural changes. In view of the important role of c-fos in devel- opment, it seems very difficult to characterize the func- tional role of c-fos-dependent signal transduction in the adult nervous system by using c-fos knock out or overexpressing transgenic animals, because a vast number of adaptive changes can be expected in the signalling pathway during development. Instead, on the basis of the existence of natural transacting anti- sense RNA molecules controlling gene expression, sin- gle stranded antisense DNA oligonucleotides were injected into the different parts of the brain including the ventricles to analyse the functional role of c-fos. The first study was carried out by Chiasson et al. (1992), demonstrating that the amphetamine-induced increase of c-fos in striatal nerve cells can be counter- acted by intrastriatal injections of c-fos antisense 425