TY - JOUR
T1 - 5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response
AU - Samuels, Benjamin Adam
AU - Anacker, Christoph
AU - Hu, Alice
AU - Levinstein, Marjorie R.
AU - Pickenhagen, Anouchka
AU - Tsetsenis, Theodore
AU - Madroñal, Noelia
AU - Donaldson, Zoe R.
AU - Drew, Liam John
AU - Dranovsky, Alex
AU - Gross, Cornelius T.
AU - Tanaka, Kenji F.
AU - Hen, René
N1 - Funding Information:
The authors thank K. Win and D. Tora for technical support, and M. Kheirbek and D. Leonardo for discussions. This work was supported by NIMH R37MH068542 (R.H.), NIMH R01MH083862 (R.H.), HDRF MPPN8883 (R.H.), NYSTEM C029157 (R.H.), NIMH K01MH098188 (B.A.S.), BBRF NARSAD Young Investigator 19658 (B.A.S.), a Charles H. Revson fellowship (B.A.S.), a German Research Foundation (DFG) postdoctoral fellowship (C.A.), NIMH T32MH015144 (Z.R.D.), NIMH R01MH01844 (A.D.), funds from EMBL (C.T.G.), and an EC Marie Curie Fellowship (N.M.).
Publisher Copyright:
© 2015 Nature America, Inc.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether mature dentate gyrus granule cells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response.
AB - Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether mature dentate gyrus granule cells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response.
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U2 - 10.1038/nn.4116
DO - 10.1038/nn.4116
M3 - Article
C2 - 26389840
AN - SCOPUS:84945433786
SN - 1097-6256
VL - 18
SP - 1606
EP - 1616
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 11
ER -