Brain Research 867 (2000) 70–79 www.elsevier.com / locate / bres Research report DNA fragmentation factor 45 deficient mice exhibit enhanced spatial learning and memory compared to wild-type control mice a a b a a, * Jill M. Slane , Han S. Lee , CharlesV. Vorhees , Jianhua Zhang , Ming Xu a Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA b Division of Developmental Biology, Children’ s Hospital Research Foundation, Cincinnati, OH 45229, USA Accepted 8 March 2000 Abstract Programmed cell death or apoptosis is a highly regulated physiological process that is critical in development, particularly in the central nervous system. The DNA fragmentation factor 45 (DFF45 or ICAD) is a subunit of a heterodimeric DNase complex that is crucial for DNA fragmentation and normal apoptosis. To examine the neurobiological consequences of lacking DNA fragmentation and timely apoptosis during mouse development in vivo, we compared spatial learning behaviors in DFF45 mutant and wild-type control mice. We found that DFF45 mutant mice exhibit enhanced spatial learning and memory compared to wild-type mice. Moreover, both the granule cell density and total granule cell number in the hippocampal dentate gyrus region are higher in the DFF45 mutant brains than in the wild-type brains. We propose that the increase in granule cell number in the dentate region due to the DFF45 mutation changes the neuronal network underlying spatial learning and memory in DFF45 mutant mice.  2000 Elsevier Science B.V. All rights reserved. Theme: Neural basis of behavior Topic: Learning and memory: systems and functions Keywords: DFF45; Spatial learning; Apoptosis; Dentate granule cells; Hippocampus; Morris water maze 1. Introduction death, including the Bcl-2 family of proteins, adapter proteins and caspases, appear to be identical to those used Programmed cell death or apoptosis is a highly regulated elsewhere [6,9,10,16,19,20,25–28,32,43]. Most of these physiological process that is critical in development, proteins are expressed not only during development but particularly in the central nervous system. Roughly half of also in adults. However, the functional significance of the neurons in mammals undergo apoptosis during normal neuronal cell death during development and continued development [33]. Neuronal cell death occurs mostly at a expression of molecules in the cell death machinery in time when neurons innervate their targets. The mecha- adults remain poorly understood. nisms for the death of such a large number of neurons DNA fragmentation and chromatin condensation are during development remain unclear. One hypothesis is that hallmarks of apoptosis. These processes have been shown an excess number of neurons compete for limited amounts to depend critically on a heterodimeric protein complex of neurotrophic factors produced by their targets. Only composed of DNA fragmentation factors 45 and 40 those neurons that are successful in the competition will (DFF45 or ICAD and DFF40 or CAD, respectively) make connections with the targets and thus survive to [11,22–24,37]. DFF45 is ubiquitously expressed during participate in the proper wiring and functioning of the early embryonic development and in adult tissues, includ- nervous system [2,17,33,35,36]. The molecular compo- ing the brain, suggesting an important role of DFF45 nents of the apoptotic machinery used in neuronal cell throughout mouse [45]. To understand the in vivo function of DFF45, we previously generated DFF45 mutant [44]. We found that DFF45-deficient cells exhibit more resist- *Corresponding author. Tel.: 11-513-558-2922; fax: 11-513-558- ance to apoptosis than wild-type control cells in response 4454. E-mail address: ming.xu@uc.edu (M. Xu) to several apoptotic stimuli [45]. These results suggest that 0006-8993 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0006-8993(00)02258-7