Diverging mechanisms for TNF-alpha receptors in normal mouse brains and in functional recovery after injury: From gene to behavior.
Cytokines, such as tumour necrosis factor (TNF)-alpha and lymphotoxin-alpha, have been described widely to play important roles in the brain in physiologic conditions and after traumatic injury. However, the exact mechanisms involved in their function have not been fully elucidated. We give some insight on their role by using animals lacking either Type 1 receptor (TNFR1KO) or Type 2 (TNFR2KO) and their controls (C57Bl/6). Both TNFR1KO and to a greater extent TNFR2KO mice showed increased exploration/activity neurobehavioral traits in the hole board test, such as rearings, head dippings, and ambulations, compared with wild-type mice, suggesting an inhibitory role of TNFR1/TNFR2 signaling. In contrast, no significant differences were observed in the elevated plus maze test, ruling out a major role of these receptors in the control of anxiety. We next evaluated the response to a freeze injury to the somatosensorial cortex. The effect of the cryolesion on motor function was evaluated with the horizontal ladder beam test, and the results showed that both TNFR1KO and TNFR2KO mice made fewer errors, suggesting a detrimental role for TNFR1/TNFR2 signaling for coping with brain damage. Expression of approximately 22600 genes was analyzed using an Affymetrix chip (MOE430A) at 0 (unlesioned), 1, or 4 days post-lesion in the three strains. The results show a unique and major role of both TNF receptors on the pattern of gene expression elicited by the injury but also in normal conditions, and suggest that blocking of TNFR1/TNFR2 receptors may be beneficial after a traumatic brain injury.
Quintana
Albert
A
Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Bellaterra, Spain.
Molinero
Amalia
A
Florit
Sergi
S
Manso
Yasmina
Y
Comes
Gemma
G
Carrasco
Javier
J
Giralt
Mercedes
M
Borup
Rehannah
R
Nielsen
Finn Cilius
FC
Campbell
Iain L
IL
Penkowa
Milena
M
Hidalgo
Juan
J
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005106:Exploratory Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D017403:In Situ Hybridization / Q000379:methods; D018782:Maze Learning / Q000502:physiology; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011597:Psychomotor Performance / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D020127:Recovery of Function / Q000235:genetics*
D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C469948:Tnfrh2 protein, mouse; C506236:Tnfrsf1a protein, mouse; D008668:Metallothionein