N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells


Evidence from epidemiological and laboratory studies, as well as randomized placebo-controlled trials, suggests supplementation with n-3 polyunsaturated fatty acids (PUFAs) may be efficacious for treatment of major depressive disorder (MDD). The mechanisms underlying n-3 PUFAs potential therapeutic properties remain unknown. There are suggestions in the literature that glial hypofunction is associated with depressive symptoms and that antidepressants may normalize glial function. In this study, induced pluripotent stem cells (iPSC)-derived neuronal stem cell lines were generated from individuals with MDD. Astrocytes differentiated from patient-derived neuronal stem cells (iNSCs) were verified by GFAP. Cells were treated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or stearic acid (SA). During astrocyte differentiation, we found that n-3 PUFAs increased GFAP expression and GFAP positive cell formation. BDNF and GDNF production were increased in the astrocytes derived from patients subsequent to n-3 PUFA treatment. Stearic Acid (SA) treatment did not have this effect. CREB activity (phosphorylated CREB) was also increased by DHA and EPA but not by SA. Furthermore, when these astrocytes were treated with n-3 PUFAs, the cAMP antagonist, RP-cAMPs did not block n-3 PUFA CREB activation. However, the CREB specific inhibitor (666-15) diminished BDNF and GDNF production induced by n-3 PUFA, suggesting CREB dependence. Together, these results suggested that n-3 PUFAs facilitate astrocyte differentiation, and may mimic effects of some antidepressants by increasing production of neurotrophic factors. The CREB-dependence and cAMP independence of this process suggests a manner in which n-3 PUFA could augment antidepressant effects. These data also suggest a role for astrocytes in both MDD and antidepressant action.

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Fig. 1: DHA and EPA treatment increased astrocyte differentiation from patient-derived iNSCs.
Fig. 2: GFAP expression was increased by n-3 PUFAs treatment during astrocyte differentiation from patient-derived iNSCs.
Fig. 3: N-3 PUFAs elevated BDNF and GDNF production in astrocytes from patient-derived iNSCs.
Fig. 4: CREB was activated by DHA or EPA treatment, and this was cAMP independent.
Fig. 5: CREB inhibitor attenuated the BDNF and GDNF increase induced by n-3 PUFAs in astrocytes.


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This research is supported by NIH R01AT009169 (MMR, JZY) and VA Merit Award BX00149 (MMR) and NIH R41MH113398 (MMR). Patient cell line collection and derivation were supported by NIH P50MH106933 and NIH R01AT009144 (RHP, SDS, JW). MMR is a VA Research Career Scientist BX004475.

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Correspondence to Jiang-Zhou Yu or Mark M. Rasenick.

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MMR has received research support from Lundbeck SA and consulting fee from Otsuka, INC. He also has ownership interest in PAX Neuroscience.

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Yu, J., Wang, J., Sheridan, S.D. et al. N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0786-5

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