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Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety,
G C Carlson1, R E Lin2, Y Chen1
1Department of Psychiatry, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31st Street, Translational Research Building, Philadelphia, PA 19104, United States; Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31st Street, Translational Research Building, Philadelphia, PA 19104, United States.
Abstract:
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.
Insights
Dexras1 knockout mice show altered working memory and sensory gating, suggesting a role in psychiatric disorders. This GTPase impacts NMDA receptor expression and may modulate specific emotional and cognitive domains.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Dexras1 is a novel GTPase implicated in signaling pathways relevant to neurological and psychiatric diseases.
- Previous research linked Dexras1 to iron trafficking and NMDA receptor-dependent neurodegeneration.
- The role of Dexras1 in normal brain function and psychiatric conditions remained largely unexplored.
Purpose of the Study:
- To investigate the function of Dexras1 in normal brain function and its potential involvement in psychiatric disease.
- To assess behavioral abnormalities and NMDA receptor subunit expression in Dexras1 knockout mice.
- To explore Dexras1's influence on emotional, sensory, and cognitive domains.
Main Methods:
- Generation and behavioral phenotyping of germline knockout (KO) mice lacking Dexras1.
- Assessment of anxiety-like behavior using open field and zero maze tests.
- Evaluation of depression-like behavior via tail suspension test.
- Testing of memory functions including novel object recognition and T-maze tasks.
- Measurement of pre-pulse inhibition (PPI) and startle response.
- Analysis of NMDA receptor subunit protein expression levels.
Main Results:
- Dexras1 KO mice did not exhibit altered baseline anxiety or depression-like behaviors.
- A significant decrement in working memory was observed in Dexras1 KO mice, while episodic memory remained unchanged.
- An increase in pre-pulse inhibition (PPI) was noted, without affecting startle amplitude or locomotor activity.
- Expression analysis revealed an increased NR2A NMDA receptor subunit in Dexras1 KO mice.
Conclusions:
- Dexras1 plays a role in modulating specific aspects of cognitive and sensory processing, including working memory and sensory gating.
- The observed changes in NMDA receptor subunit expression suggest a mechanism by which Dexras1 influences neuronal function.
- These findings indicate a potential role for Dexras1 in psychiatric symptom modulation, possibly through interactions with NMDA receptors and other disease-related partners.
