Age-dependent maintenance of motor control and corticostriatal innervation by death receptor 3.
Death receptor 3 is a proinflammatory member of the immunomodulatory tumor necrosis factor receptor superfamily, which has been implicated in several inflammatory diseases such as arthritis and inflammatory bowel disease. Intriguingly however, constitutive DR3 expression has been detected in the brains of mice, rats, and humans, although its neurological function remains unknown. By mapping the normal brain expression pattern of DR3, we found that DR3 is expressed specifically by cells of the neuron lineage in a developmentally regulated and region-specific pattern. Behavioral studies on DR3-deficient (DR3(ko)) mice showed that constitutive neuronal DR3 expression was required for stable motor control function in the aging adult. DR3(ko) mice progressively developed behavioral defects characterized by altered gait, dyskinesia, and hyperactivity, which were associated with elevated dopamine and lower serotonin levels in the striatum. Importantly, retrograde tracing showed that absence of DR3 expression led to the loss of corticostriatal innervation without significant neuronal loss in aged DR3(ko) mice. These studies indicate that DR3 plays a key nonredundant role in the retention of normal motor control function during aging in mice and implicate DR3 in progressive neurological disease.
Twohig
Jason Peter
JP
Department of Infection, Immunity & Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Roberts
Malcolm I
MI
Gavalda
Nuria
N
Rees-Taylor
Emma L
EL
Giralt
Albert
A
Adams
Debbie
D
Brooks
Simon P
SP
Bull
Melanie J
MJ
Calder
Claudia J
CJ
Cuff
Simone
S
Yong
Audrey A
AA
Alberch
Jordi
J
Davies
Alun
A
Dunnett
Stephen B
SB
Tolkovsky
Aviva M
AM
Wang
Eddie C Y
EC
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002450:Cell Communication / Q000235:genetics / Q000502:physiology; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D003342:Corpus Striatum / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009048:Motor Skills / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D018377:Neurotransmitter Agents; D053219:Receptors, Tumor Necrosis Factor, Member 25