RGD Reference Report - Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction. - Rat Genome Database

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Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction.

Authors: Kobori, N  Hu, B  Dash, PK 
Citation: Kobori N, etal., Neuroscience. 2011 Jan 13;172:293-302. Epub 2010 Oct 23.
RGD ID: 5688366
Pubmed: PMID:20974230   (View Abstract at PubMed)
PMCID: PMC3010433   (View Article at PubMed Central)
DOI: DOI:10.1016/j.neuroscience.2010.10.048   (Journal Full-text)

The prefrontal cortex is highly vulnerable to traumatic brain injury (TBI) and its structural and/or functional alterations as a result of TBI can give rise to persistent working memory (WM) dysfunction. Using a rodent model of TBI, we have described profound WM deficits following TBI that are associated with increases in prefrontal catecholamine (both dopamine and norepinephrine) content. In this study, we examined if enhanced norepinephrine signaling contributes to TBI-associated WM dysfunction. We demonstrate that administration of alpha1 adrenoceptor antagonists, but not alpha2A agonist, at 14 days post-injury significantly improved WM performance. mRNA analysis revealed increased levels of alpha1A, but not alpha1B or alpha1D, adrenoceptor in the medial prefrontal cortex (mPFC) of brain-injured rats. As alpha1A and 1B adrenoceptor promoters contain putative cAMP response element (CRE) sequences, we therefore examined if CRE-binding protein (CREB) actively engages these sequences in order to increase receptor gene transcription following TBI. Our results show that the phosphorylation of CREB is enhanced in the mPFC at time points during which increased alpha1A mRNA expression was observed. Chromatin immunoprecipitation (ChIP) assays using mPFC tissue from injured animals indicated increased phospho-CREB binding to the CRE sites of alpha1A, but not alpha1B, promoter compared to that observed in uninjured controls. To address the translatability of our findings, we tested the efficacy of the FDA-approved alpha1 antagonist Prazosin and observed that this drug improves WM in injured animals. Taken together, these studies suggest that enhanced CREB-mediated expression of alpha1 adrenoceptor contributes to TBI-associated WM dysfunction, and therapies aimed at reducing alpha1 signaling may be useful in the treatment of TBI-associated WM deficits in humans.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ADRA1AHumanBrain Injuries  ISOAdra1a (Rattus norvegicus)mRNA:increased expression:frontal cortexRGD 
Adra1aRatBrain Injuries  IEP mRNA:increased expression:frontal cortexRGD 
Adra1aMouseBrain Injuries  ISOAdra1a (Rattus norvegicus)mRNA:increased expression:frontal cortexRGD 
ADRA1AHumanMemory Disorders  ISOAdra1a (Rattus norvegicus)associated with brain injuriesRGD 
Adra1aRatMemory Disorders  IDA associated with brain injuriesRGD 
Adra1aMouseMemory Disorders  ISOAdra1a (Rattus norvegicus)associated with brain injuriesRGD 

Objects Annotated

Genes (Rattus norvegicus)
Adra1a  (adrenoceptor alpha 1A)

Genes (Mus musculus)
Adra1a  (adrenergic receptor, alpha 1a)

Genes (Homo sapiens)
ADRA1A  (adrenoceptor alpha 1A)


Additional Information