Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens.
The etiology of major depression remains unknown, but dysfunction of serotonergic signaling has long been implicated in the pathophysiology of this disorder. p11 is an S100 family member recently identified as a serotonin 1B [5-hydroxytryptamine 1B (5-HT(1B))] and serotonin 4 (5-HT(4)) receptor-binding protein. Mutant mice in which p11 is deleted show depression-like behaviors, suggesting that p11 may be a mediator of affective disorder pathophysiology. Using somatic gene transfer, we have now identified the nucleus accumbens as a key site of p11 action. Reduction of p11 with adeno-associated virus (AAV)-mediated RNA interference in the nucleus accumbens, but not in the anterior cingulate, of normal adult mice resulted in depression-like behaviors nearly identical to those seen in p11 knockout mice. Restoration of p11 expression specifically in the nucleus accumbens of p11 knockout mice normalized depression-like behaviors. Human nucleus accumbens tissue shows a significant reduction of p11 protein in depressed patients when compared to matched healthy controls. These results suggest that p11 loss in rodent and human nucleus accumbens may contribute to the pathophysiology of depression. Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value.
Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
Brian
B
Alexander
Jennifer
J
Warner-Schmidt
Therese
T
Eriksson
Carol
C
Tamminga
Margarita
M
Arango-Lievano
Margarita
M
Arango-Llievano
Subroto
S
Ghose
Mary
M
Vernov
Mihaela
M
Stavarache
Mihaela
M
Stavarche
Sergei
S
Musatov
Marc
M
Flajolet
Per
P
Svenningsson
Paul
P
Greengard
Michael G
MG
Kaplitt
D000818:Animals; D017306:Annexin A2 / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D003863:Depression / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D009714:Nucleus Accumbens / Q000378:metabolism*; D009418:S100 Proteins / Q000235:genetics*; D000099248:S100 Calcium Binding Protein A10
D017306:Annexin A2; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10