title: Temporal course of changes in gene expression suggests a cytokine-related mechanism for long-term hippocampal alteration after controlled cortical impact.
abstract: Mild traumatic brain injury (mTBI) often has long-term effects on cognitive function and social behavior. Altered gene expression may be predictive of long-term psychological effects of mTBI, even when acute clinical effects are minimal or transient. Controlled cortical impact (CCI), which causes concussive, but nonpenetrant, trauma to underlying (non-cortical) brain, resulting in persistent changes in hippocampal synaptic function, was used as a model of mTBI. The hippocampal transcriptomes of sham-operated or injured male rats at 1, 7, and 30 days postinjury were examined using microarrays comprising a comprehensive set of expressed genes, subsequently confirmed by quantitative reverse-transcriptase polymerase chain reaction. Transcripts encoding the chemokines, chemokine (C-C motif) ligand (Ccl)2 and Ccl7, inflammatory mediators lipocalin-2 (Lcn2) and tissue inhibitor of metalloproteinase 1 (Timp1), immunocyte activators C-C chemokine receptor type 5 (Ccr5) and Fc fragment of IgG, low affinity IIb, receptor (CD32) (Fcgr2b), the major histocompatibility complex II immune response-related genes, Cd74 and RT1 class II, locus Da (RT1-Da), the complement component, C3, and the transcription factor, Kruppel-like factor 4 (Klf4), were identified as early (Ccl2, Ccl7, Lcn2, and Timp1), intermediate (Ccr5, Fcgr2b, Cd74, RT1-Da, and C3), and late (Klf4) markers for bilateral hippocampal response to CCI. Ccl2 and Ccl7 transcripts were up-regulated within 24 h after CCI, and their elevation subsided within 1 week of injury. Other transcriptional changes occurred later and were more stable, some persisting for at least 1 month, suggesting that short-term inflammatory responses trigger longer-term alteration in the expression of genes previously associated with injury, aging, and neuronal function in the brain. These transcriptional responses to mTBI may underlie long-term changes in excitatory and inhibitory neuronal imbalance in hippocampus, leading to long-term behavioral consequences of mTBI.
authors.affiliation: 1 Program in Neuroscience, F. Edward Hébert School of Medicine Uniformed Services University of the Health Sciences , Bethesda, Maryland.
authors.forename: Camila P
authors.initials: CP
authors.lastname: Almeida-Suhett
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Ann M
authors.initials: AM
authors.lastname: Marini
authors.forename: Maria F M
authors.initials: MF
authors.lastname: Braga
authors.forename: Lee E
authors.initials: LE
authors.lastname: Eiden
mesh_terms: D000818:Animals; D001924:Brain Concussion / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D000090062:Kruppel-Like Factor 4; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D059467:Transcriptome