Similarities and dissimilarities in the effects of benzodiazepines and specific serotonin reuptake inhibitors (SSRIs) in the defensive marble burying test: A systematic review and meta-analysis.

One problem areas of animal models and tests for neuropsychiatric disorders is unclear reproducibility, including both internal and external validity. One way to examine external validity is with systematic reviews and meta-analyses, a standard practice in clinical research that is relatively neglected in preclinical research. Considering the need to evaluate the validity and reproducibility of frequently used animal models, this study presents a meta-analysis of the effects of prototypic benzodiazepines and specific serotonin reuptake inhibitors (SSRIs) in the mouse defensive marble burying test (MBT). These drug groups were selected because although they differ in their biological targets as well as in their clinical use, they are both commonly used for the treatment of anxiety disorders. A PubMed literature search was performed to identify studies that examined the effects of benzodiazepines (diazepam, alprazolam, chlordiazepoxide, clonazepam) or SSRIs (fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine) in the MBT in mice. For benzodiazepines, 73 experiments were included. Benzodiazepines effect size was 2.04 and Q statistics was 1959 with a significant correlation between dose and effect size (r = 0.31, p = 0.007). For SSRIs we identified 47 experiments. Effect size of SSRIs was 2.24 and Q statistics was 493.38. No correlation was found between dose and effect size (r = 0.23, p = 0.12). The current results support the external validity of the defensive marble burying test as a screening test for anxiolytic effects. However, these results indicate that significant attention should be given to the administration schedules of benzodiazepines and SSRIs.

Gene dosage of the transcription factor Fingerin (bHLHA9) affects digit development and links syndactyly to ectrodactyly.

Distal limb deformities are congenital malformations with phenotypic variability, genetic heterogeneity and complex inheritance. Among these, split-hand/foot malformation is an ectrodactyly with missing central fingers, yielding a lobster claw-like hand, which when combined with long-bone deficiency is defined as split-hand/foot malformation and long-bone deficiency (SHFLD) that is genetically heterogeneous. Copy number variation (CNV) consisting of 17p13.3 duplication was identified in unrelated pedigrees, underlying SHFLD3 (OMIM 612576). Although the transcription factor Fingerin (bHLHA9) is the only complete gene in the critical region, its biological role is not yet known and there are no data supporting its involvement in mammalian limb development. We have generated knockout mice in which only the entire coding region of Fingerin was deleted, and indeed found that most null mice display some limb defects. These include various levels of simple asymmetrical syndactyly, characterized by webbed fingers, generated by incomplete separation of soft, but not skeletal, tissues between forelimb digits 2 and 3. As expected, hand pads of Fingerin null embryos exhibited reduced apoptosis between digital rays 2 and 3. This defect was shown to cause syndactyly when the same limbs were grown ex vivo following the apoptosis assay. Extrapolating from mouse data, we suggest that Fingerin loss-of-function in humans may underlie MSSD syndactyly (OMIM 609432), which was mapped to the same locus. Taken together, Fingerin gene dosage links two different congenital limb malformations, syndactyly and ectrodactyly, which were previously postulated to share a common etiology. These results add limb disorders to the growing list of diseases resulting from CNV.