Brain pathways mediating the pro-aggressive effect of the steroid sulfatase (Sts) gene.

STS is the single enzyme that converts all steroid sulfates into their free steroid forms. Initiation of attack behavior against conspecific male mice appeared to be linked to Sts. Here we have confirmed the role of Sts through an association study with attack behavior. Previous studies indicated a positive correlation between the initiation of attack behavior and liver STS concentration levels in male mice, but this finding was not compatible with established knowledge of STS mechanisms. High STS concentrations induce low concentrations of sulfated steroids. Sulfated and un-sulfated steroids are GABA(A) receptor agonists and NMDA receptor positive allosteric modulators. This synaptic pattern of functioning can generate attack behavior and we have confirmed here that an injection of the sulfated steroid dehydroepiandrosterone sulfate (DHEA-S) increases attack behavior. To solve the paradox, we measured the transcription activity of the genes underlying the pathways involved in the hydrolysis of sulfated steroids and leading to the formation of un-conjugated steroids in the mouse brain. We observed that the genes monitoring the steroid biosynthesis pathways exhibited a transcription pattern resulting in an increased sulfotransferase activity in the attacking males that could counterbalance the de-sulfating activity of Sts in the attacking mice.

Pre-weaning sensorial and motor development in mice transpolygenic for the critical region of trisomy 21.

Trisomy 21 occurs every 1/800 births and is the most frequent genetic cause of mental retardation. Children with trisomy 21 show delayed sensorial and motor development as well as cognitive disorders. We selected a mouse model of trisomy 21 (TRS21): transgenic mice carrying extra copies of a HSA21 region corresponding to the D21S17-ETS2 region (previously referred to as "Down syndrome critical region 1"). Sensorial and motor development was measured in these partially transgenic mice, from birth to weaning. The four HSA21 regions contributed unequally to sensorial and motor development delay. The more centromeric region (230E8) modified 4 of the development indicators plus the size of the effect, indicated by partial eta(2)(eta(p)(2), reached a median value of 14.5%. The neighboring 141G6 region contributed to 5 developmental differences (eta(p)(2) median value 14%). The most telomeric region (285E6) only modified one development indicator. An extra copy of an HSA21 fragment (referred to here as the 152F7 region) induced modifications to 14 of the 18 indicators measured with a eta(2) median value reaching 20%. The results indicate a noticeable contribution of the 152F7 region to sensorial and motor development. The contribution of this region to cognitive functioning and its neurobiological basis has been already reported. This set of result suggests the location in the D21S17-ETS2 region of several genes playing crucial role in cognitive and developmental impairment observed in TRS21.

Functional analysis of genes implicated in Down syndrome: 2. Laterality and corpus callosum size in mice transpolygenic for Down syndrome chromosomal region -1 (DCR-1).

The association between atypical laterality and mental retardation has been reported several times, particularly in Down syndrome (DS). We investigated common genetic correlates of these components of the syndrome, examining direction (number of right paw entries in the Collins test) and degree (absolute difference between the number of right paw entries and the number of left paw entries) in mice that had incorporated extra-contiguous HSA21 fragments covering DCR-1 (Down Chromosomal Region-1). As corpus callosum size is substantially reduced in DS, and as the structure has been suspected of playing a role in atypical laterality, we also measured the corpus callosum in these mice. Extra copies of two regions (F7 and E6) have been associated with an atypical degree of laterality (strongly reduced degree). Extra copies of E8, G6 and E6 are also linked to the reduced size of the corpus callosum, indicating that the abnormal number of fibers linking the two hemispheres is not associated with atypical laterality in DS. Together, these results indicate that some of the genes involved in atypical laterality and in the reduced size of the corpus callosum in DS are present on DCR-1. An extra copy of F7 and, to a lesser extent, an extra copy of E6, are also associated with cognitive impairment. These results support the hypothesis of common genetic correlates in atypical laterality and mental retardation in DS.