Behavioural Brain Research 142 (2003) 135–142 Protective effect of 5-HT1B receptor gene deletion on the age-related decline in spatial learning abilities in mice Marie-Christine Buhot a,∗ , Mathieu Wolff a , Magdaléna Savova a , Gaël Malleret a , René Hen b , Louis Segu a a Laboratoire de Neurosciences Cognitives, CNRS UMR 5106, Université de Bordeaux 1, Avenue des Facultés, 33405 Talence Cedex, France b Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA Received 13 September 2002; received in revised form 25 November 2002; accepted 25 November 2002 Abstract We previously observed that 5 months old serotonin 1B receptor knockout (5-HT1BKO) mice exhibited a facilitation of learning in a long-term spatial memory task in a water maze. In this study, we attempted to assess whether this effect might persist during aging. We compared the performances of young-adult (3 months old) and aged (22 months old) 5-HT1BKO and wild type (WT) mice in the same task. Young-adult and aged KO mice exhibited facilitated acquisition of the reference memory task as compared to their respective WT controls. Generally, the performance of aged KO was similar to that of young-adult WT on the parameters defining performance and motor (swim speed) aspects of the task. During probe trials, all mice presented a spatial selectivity, which was, however, less pronounced in aged than in young-adult WT. No such age-related effect was observed in KO mice. In a massed spatial learning task, aged KO and WT mice globally exhibited the same level of performance. Nevertheless, young-adult and aged KO mice were superior to their WT controls as concerns the working memory component of the task. The data suggest that 5-HT1BKO mice are more resistant than WT to age-related memory decline as concerns both reference/long-term and working/short-term spatial memory. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Aging; Learning and memory; Serotonin; 5-HT1B; Knockout mice; Hippocampus; Morris water maze 1. Introduction Memory capabilities that depend on the functional in- tegrity of the hippocampus appear to be particularly vulner- able to the aging process [13]. Pharmacological strategies currently being pursued in Alzheimer’s disease (AD) re- search aim to attenuate memory deficits which have been primarily attributed to the progressive degeneration of the basal forebrain cholinergic projections [27,31]. Age-induced cognitive dysfunctions are correlated to a combination of disturbances in both cholinergic and serotonergic functions [21,25]. The functional interaction between these neuro- transmitter systems plays an important role in learning and memory performance [11,28]. Concurrent loss of cholin- ergic and serotonergic transmission has been reported to result in persistent memory impairments in rat, as com- pared to the loss of cholinergic transmission alone [19]. Intrahippocampal cografts of fetal cholinergic and seroton- ∗ Corresponding author. Tel.: +33-5-56-84-87-09; fax: +33-5-56-84-87-43. E-mail address: buhot@neurocog.u-bordeaux.fr (M.-C. Buhot). ergic neurons are able to reduce impairments in long-term spatial memory induced by extensive lesions of the dorsal septo-hippocampal pathway [3]. The 5-HT1B receptor can be considered as a key target by which 5-HT is able to modulate hippocampal-dependent learning and memory [7,8]. Rats receiving a stimulation of hippocampal (CA1) 5-HT1B receptors were found to be impaired in a spatial learning task, exhibiting more reference than working memory errors [9]. These data suggest that the inactivation of 5-HT1B receptors might have positive effects on hippocampal functions. The lack of availability of specific 5-HT1B antagonists has led us to adopt a molecular biological strategy for study- ing the implication of 5-HT1B receptor in cognitive func- tions, by using 5-HT1B receptor knockout (5-HT1BKO) mice [26] as subjects in different hippocampal-dependent and -independent learning tasks [18]. In the (classical) long-term spatial version of the Morris water maze, adult 5-HT1BKO mice showed facilitation in learning the task, as compared to their wild type (WT) controls, but this effect was not observed in a massed spatial learning assessing more short-term memory [18]. Furthermore, 5-HT1BKO 0166-4328/02/$ – see front matter © 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0166-4328(02)00400-X