CREB deletion increases resilience to stress and downregulates inflammatory gene expression in the hippocampus
Melissa T Manners1, Julia K Brynildsen1, Max Schechter1
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Insights
Cyclic AMP response element (CRE)-binding protein (CREB) regulates immune genes in the hippocampus. CREB-deficient mice showed resilience to depression-like stress, suggesting CREB
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- The transcription factor CREB (cyclic AMP response element (CRE)-binding protein) is crucial in depression pathophysiology and treatment.
- Hippocampal abnormalities are linked to depression, but the specific genes regulated by CREB in this region remain largely unidentified.
- Understanding CREB's role in regulating gene expression is key to developing novel depression therapies.
Purpose of the Study:
- To comprehensively identify genes actively translated and regulated by CREB in the mouse hippocampus.
- To investigate the behavioral and molecular consequences of CREB deficiency in the hippocampus, particularly under stress conditions.
- To explore the potential of CREB-regulated immune and inflammatory pathways as therapeutic targets for depression.
Main Methods:
- Utilized translating ribosome affinity purification (TRAP) in wild-type and CREB-deficient mice to isolate actively translating mRNAs.
- Employed CrebloxP/loxP; RosaLSL-GFP-L10a mice for CREB deletion and GFP-tagged ribosome capture, enabling whole-genome transcript identification.
- Administered unpredictable chronic mild stress (UCMS) to assess behavioral and molecular responses in CREB-deficient and control mice.
Main Results:
- Identified over 200 downregulated genes in CREB-deficient hippocampi, primarily associated with inflammation and immune system functions, including toll-like receptor 1 (TLR1).
- CREB-deficient mice exhibited resilience to the physiological and affective behavioral effects of UCMS, indicating a protective role of CREB absence under stress.
- UCMS increased TLR1 expression in control mice, but this response was blunted in CREB-deficient mice, highlighting CREB's role in stress-induced immune modulation.
Conclusions:
- CREB significantly regulates a broad spectrum of immune and inflammatory genes within the hippocampus.
- Disruption of CREB-mediated gene regulation confers resilience to depression-like behaviors induced by chronic stress.
- Targeting CREB-regulated immune and inflammatory pathways represents a promising therapeutic strategy for depression treatment.
Abstract:
The transcription factor CREB (cyclic AMP response element (CRE)-binding protein) is implicated in the pathophysiology and treatment of depression. Structural and functional studies in both animals and humans suggest that abnormalities of the hippocampus may play a role in depression. CREB regulates thousands of genes, yet to date, only a handful that mediate depression or antidepressant response have been identified as relevant CREB targets. In order to comprehensively identify genes regulated by CREB in the hippocampus, we employed translating ribosome affinity purification (TRAP) to detect actively translating mRNAs in wild type and CREB-deficient mice. Using CrebloxP/loxP; RosaLSL-GFP-L10a mice, we conducted whole genome sequencing to identify transcripts only in cells that lack CREB, as introduction of Cre-recombinase simultaneously deleted CREB and expressed GFP-tagged L10a ribosomes that enabled TRAP. We identified over 200 downregulated genes predominantly associated with inflammation and the immune system, including toll-like receptor 1 (TLR1). To determine if baseline disruption in gene expression in the hippocampus of CREB-deficient mice can modulate behavior, we used unpredictable chronic mild stress (UCMS) to produce a set of behavioral alterations with strong validity for depression. We found that CREB-deficient mice demonstrated resilience to the physiological effects of UCMS and also showed changes in affective behaviors specifically in the presence of stress. TLR1 expression was increased following UCMS in control but not in CREB-deficient mice. The results suggest that CREB-mediated regulation of immune system and inflammatory factors may provide additional targets for the treatment of depression.
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