Using the phage P1-derived Cre/loxP recombination system, we have developed a method to create mice in which the deletion (knockout) of virtually any gene of interest is restricted to a subregion or a specific cell type in the brain such as the pyramidal cells of the hippocampal CA1 region. The Cre/loxP recombination-based gene deletion appears to require a certain level of Cre protein expression. The brain subregional restricted gene knockout should allow a more precise analysis of the impact of a gene mutation on animal behaviors.

Calcineurin (CN), a calcium-and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.C alcineurin (CN), also called protein phosphatase 2B, is a heterodimeric Ca 2ϩ ͞calmodulin-dependent serine͞threonine protein phosphatase composed of CNB regulatory and CNA catalytic subunits (1). Originally identified in the brain, CN was later found to play a critical role in T cell function, through activation of nuclear factor of activated T cell-mediated transcription of cytokine genes, including the IL-2 gene (2, 3). This action of CN comprises a target for the immunosuppressants, cyclosporin A and FK506, which associate with immunophilins and bind to and inactivate CN. More recently, CN has been shown to play an important role in CNS functions, including neurite extension, synaptic plasticity and learning and memory (4, 5).We previously reported a severe and specific working memory deficit of forebrain specific CNB-deficient mice (CN mutant mice) as assessed by delayed matching to place Morris water maze and eight-arm radial maze paradigms (5). To further investigate the behavioral significance of CN, CN mutant mice were subjected to a comprehensive behavioral test battery (6, 7). CN mutant mice display a spectrum of abnormalities that is strikingly similar to those observed in schizophrenia patients. In addition, a number of supporting lines of evidence are consistent with the possibility that alterations in CN function occur in schizophrenia. Furthermore, in our accompanying paper, we investigated the potential involvement of altered CN signaling in genetic susceptibility to schizophrenia, and we report evidence supporting association of the PPP3CC gene encoding the CNA␥ catalytic subunit with disease (8). Based on these findings, we propose that alterations affecting CN signaling could comprise an important contributing factor in schizophrenia pathogenesis. Materials and MethodsAnimals and Experimental Design. The generation of the CN mutants is detailed elsewhere (5). The background strain used to generate the mutation was C57BL͞6J. All mutant and control mice were in a pure C57BL͞6J background. All CN mutant mice consisted of homozygous floxed, heterozygous Cre recombinase transgenic mice. All control mice consisted of homozygous or heterozygous floxed, Cre transg...

There appear to be robust changes in brain volume in bipolar disorder compared with healthy volunteers, although most changes do not seem to be diagnostically specific. Age and duration of illness appear to be key issues in determining the magnitude of observed effect sizes.