Fig. 4: Neurensin-2 in PV cells mediates the behavioral response to SSRIs.

a Schematic of the viral injection strategy. AAVs were injected bilaterally to the DG (in green) of PV-Cre mice. b Experimental design for viral expression of Neurensin-2, followed by chronic fluoxetine treatment and behavioral tests. c Representative images showing GFP expressing PV cells in the DG, 21 days after AAV2-FLEX-GFP injection. Scale bar, 50 μm. GCL granule cell layer. d–f Mice with viral-mediated overexpression of GFP or Neurensin-2 (Nrsn2 O/E) in DG PV cells were treated with vehicle (veh) or fluoxetine (flx) for 21 days (d) NSF. Two-way ANOVA; interaction F (1, 51) = 3.05, P = 0.087; virus, F = 4.4, P = 0.04; treatment, F = 6.18, p = 0.012. *p = 0.025, n = 13, 13, 16, 13. e TST. Two-way ANOVA; interaction, F (1, 49) = 5.19, P = 0.027; virus, F = 4.41, P = 0.040; treatment, F = 21.4, P < 0.0001. *p = 0.016, ****p < 0.0001. n = 13, 13, 16, 11. f FST. Two-way ANOVA; Interaction F (1, 51) = 5.31, P = 0.025; virus, F = 3.16, P = 0.08; treatment, F = 7.24, P = 0.009. **p = 0.004, *p = 0.023, n = 13, 13, 16, 13. g, h WT mice or mice with a constitutive deletion of Neurensin-2 (Nrsn2-KO) were treated for 21 days with vehicle (veh) or fluoxetine (flx) and tested behaviorally. g NSF. Two-way ANOVA; interaction, F (1, 104) = 1.99, P = 0.16; genotype, F (1, 104) = 6.62, P = 0.011; treatment, F (1, 104) = 25.8, P < 0.0001. *p = 0.039, #p = 0.038, ****p < 0.0001, n = 34, 25, 25, 24. h TST. Two-way ANOVA; interaction, F (1, 100) = 0.39, P = 0.53; genotype, F = 0.021, P = 0.88; treatment, F = 22.1, P < 0.0001. *p = 0.018, ***p = 0.0002, n = 31, 25, 25, 23. i Bar graph showing qPCR analysis of hippocampal Bdnf mRNA from WT and Nrsn2-KO mice. Unpaired t test, *p = 0.017 for Bdnf, n = 5–6/group.