Recent studies have shown that stress affects neuronal maturation (Tamura et al., 2011), as well as KCC2 expression and function in neurons (Hewitt et al., 2009; Wake et al., 2007). Therefore, we explored whether behavioral manipulations also modulate the impact of DISC1 function during early postnatal neurogenesis using a well-established maternal deprivation stress paradigm (Figure 6A) (Meaney et al., 1996). Ca2+ imaging analysis showed a significant muscimol-induced Ca2+ rise of new neurons at 7 dpi after stress (Figure S6A), suggesting a delayed polarity shifting of GABA responses. Importantly, shRNA-D1/GFP+ neurons at 7 dpi exhibited accelerated dendritic growth after maternal deprivation stress, but not after the sham treatment (Figures 6B to 6D). Interestingly, after maternal deprivation stress, shRNA-D1/GFP+ neurons, but not shRNA-C1/GFP+ neurons, also exhibited soma hypertrophy, ectopic primary dendrites, and aberrant neuronal positioning at 7 dpi (Figures S6B to S6D), resembling the full array of neurodevelopment defects observed during adult neurogenesis. Given the lack of effects from either maternal deprivation stress or DISC1 KD alone, our result provides a striking example of a synergistic interaction between environmental contributions and genetic susceptibility in regulating neuronal development.
