Conditional deletion of Bmal1 modestly alters acute pathology without affecting functional recovery after contusive...

Germline deletion of the core circadian transcription factor Bmal1 has been shown to reduce blood-spinal cord barrier (BSCB) disruption and tissue loss following moderate T9 contusive spinal cord injury (SCI) in mice. Therefore, effects of conditional Bmal1 deletions were tested using the same model. A strong reduction of Bmal1 expression in the brain or spinal cord followed tamoxifen treatment of Bmal1^loxp/loxp young adult mice who carried the broadly expressed Cag-CreERT2 recombinase transgene. Supporting functional consequences of such a deficit, canonical BMAL1 target genes Nr1d1 and Dbp were also downregulated. However, only few tissue damage markers were moderately reduced at 3 days post SCI. Furthermore, neither locomotor recovery nor long-term white matter sparing was improved. Similar SCI phenotype was observed in endothelia-selective Bmal1^-/- mice (Cdh5-Cre:Bmal1^loxp/loxp) including modest attenuation of few acute injury markers, but no significant effects on functional recovery or long-term tissue sparing. These data suggest that germline deletion of Bmal1 is protective against SCI due to compensatory changes in gene expression that originate during development and involve cells beyond endothelia. Therefore, a direct role for BMAL1 in secondary injury cascades that are activated after SCI is unlikely.