Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating.

Dexras1 is a novel GTPase that acts at a confluence of signaling mechanisms associated with psychiatric and neurological disease including NMDA receptors, NOS1AP and nNOS. Recent work has shown that Dexras1 mediates iron trafficking and NMDA-dependent neurodegeneration but a role for Dexras1 in normal brain function or psychiatric disease has not been studied. To test for such a role, mice with germline knockout (KO) of Dexras1 were assayed for behavioral abnormalities as well as changes in NMDA receptor subunit protein expression. Because Dexras1 is up-regulated during stress or by dexamethasone treatment, we included measures associated with emotion including anxiety and depression. Baseline anxiety-like measures (open field and zero maze) were not altered, nor were depression-like behavior (tail suspension). Measures of memory function yielded mixed results, with no changes in episodic memory (novel object recognition) but a significant decrement on working memory (T-maze). Alternatively, there was an increase in pre-pulse inhibition (PPI), without concomitant changes in either startle amplitude or locomotor activity. PPI data are consistent with the direction of change seen following exposure to dopamine D2 antagonists. An examination of NMDA subunit expression levels revealed an increased expression of the NR2A subunit, contrary to previous studies demonstrating down-regulation of the receptor following antipsychotic exposure (Schmitt et al., 2003) and up-regulation after exposure to isolation rearing (Turnock-Jones et al., 2009). These findings suggest a potential role for Dexras1 in modulating a selective subset of psychiatric symptoms, possibly via its interaction with NMDARs and/or other disease-related binding-partners. Furthermore, data suggest that modulating Dexras1 activity has contrasting effects on emotional, sensory and cognitive domains.

Strain differences in the effects of chronic corticosterone exposure in the hippocampus.

Stress hormones are thought to be involved in the etiology of depression, in part, because animal models show they cause morphological damage to the brain, an effect that can be reversed by chronic antidepressant treatment. The current study examined two mouse strains selected for naturalistic variation of tissue regeneration after injury for resistance to the effects of chronic corticosterone (CORT) exposure on cell proliferation and neurotrophin mobilization. The wound healer MRL/MpJ and control C57BL/6J mice were implanted subcutaneously with pellets that released CORT for 7 days. MRL/MpJ mice were resistant to reductions of hippocampal cell proliferation by chronic exposure to CORT when compared to vulnerable C57BL/6J mice. Chronic CORT exposure also reduced protein levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of C57BL/6J but not MRL/MpJ mice. CORT pellet exposure increased circulating levels of CORT in the plasma of both strains in a dose-dependent manner although MRL/MpJ mice may have larger changes from baseline. The strains did not differ in circulating levels of corticosterone binding globulin (CBG). There were also no strain differences in CORT levels in the hippocampus, nor did CORT exposure alter glucocorticoid receptor or mineralocorticoid receptor expression in a strain-dependent manner. Strain differences were found in the N-methyl-D-aspartate (NMDA) receptor, and BDNF I and IV promoters. Strain and CORT exposure interacted to alter tropomyosine-receptor-kinase B (TrkB) expression and this may be a potential mechanism protecting MRL/MpJ mice. In addition, differences in the inflammatory response of matrix metalloproteinases (MMPs) may also contribute to these strain differences in resistance to the deleterious effects of CORT to the brain.