Ž . Brain Research 832 1999 188–194 Interactive report Bcl-2 transgenic mice with increased number of neurons have a greater learning capacity 1 Grahame J. Coleman a , C.C.A. Bernard b , Ora Bernard c, ) a Department of Psychology, Monash UniÕersity, Caulfield, Vic. 3145, Australia b Neuroimmunology Laboratory, Department of Psychology, La Trobe UniÕersity, Bundoora, Vic. 3083, Australia c The Walter and Eliza Hall Institute of Medical Research, Post Office, The Royal Melbourne Hospital, Vic. 3050, Australia Accepted 23 March 1999 Abstract Transgenic mice overexpressing Bcl-2 in their neurons have an increased number of neurons. To assess whether this increased number of neurons leads to increased learning capacity we have used the Hebb–Williams maze which provides a measure of learning suitable for the study of small animals. We have demonstrated that bcl-2 transgenic mice learn faster and are more accurate in this maze. They required fewer trials to complete the maze and committed fewer errors. The transgenic mice were also faster than the wildtype mice, in particular the older mice. Prior to learning both groups of mice behaved in a similar way. These results show that bcl-2 transgene expression enhances learning capacity in mice by increasing the number of neurons. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Bcl-2; Transgenic mouse; Neuron; Learning; Maze; Behavior 1. Introduction Programmed cell death or apoptosis is a process of cell suicide which removes damaged or old cells. This active process regulates cell numbers during development and in adulthood. During the development of the nervous system, w x as many as 85% of neurons undergo cell death 20 . This developmental cell death and survival is regulated in part by neurotrophic factors which are secreted in limited amounts by their synaptic targets and for which nerve wx terminals compete to ensure survival 1 . The intracellular events involved in neuronal survival are not yet elucidated, but it is likely that members of the Bcl-2 family play an important role during development and throughout adult life. The family of Bcl-2-related proteins can be divided into Ž w x two groups: those that promote cell survival Bcl-2 26 , wx wx. Bcl-xL 3 and Bcl-w 8 and those that promote cell death Ž w x w x wx . Bax 19 , Bad 28 , Bak 4 and others . We and others have generated transgenic mice express- w x ing human Bcl-2 uniquely in neurons 7,14 . Dorsal root ) Corresponding author. Tel.: q61-3-9345-2494; Fax: q61-3-9347- 0852; E-mail: bernard@wehi.edu.au 1 Published on the World Wide Web on 26 April 1999. ganglia neurons from newborn transgenic mice showed enhanced survival in vitro in the absence of nerve growth Ž . factor NGF and motor neurons were protected from cell death following axotomy of the sciatic nerve. Recently we have also demonstrated that neurons from these mice are resistant to a variety of neurotoxins. Cultured cortical neurons from transgenic, but not from normal mice, are Ž resistant to the toxic effects of 6-hydroxydopamine 6- . Ž . OHDA and 1-methyl-4-phenylpyridinium MPP q . Ad- ministration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri- Ž . dine MPTP to normal mice which resulted in reduced level of dopamine in their substantia nigra, had no effect on the levels of dopamine in the bcl-2 transgenic mice w x 18 . In addition, the Purkinje cells of newborn transgenic mice exposed to ethanol are resistant to its toxic effect, wx while normal mice are not 9 . These transgenic mice have increased number of neurons when compared to normal mice only in neuronal populations that express the trans- gene. These neuronal populations include dorsal root gan- glia, the mesencephalic nucleus of the trigerminal nerve wx w x 7 , Purkinje cells 9,29 and inferior olivary neurons but w x not granule cells that do not express the transgene 2,29 . The increase in neuronal number indicates that Bcl-2 has protective effect during the period of naturally occurring cell death and suggests that all the neurons that express the 0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 99 01498-5