Fig. 1.

The resilient phenotype shows dramatically increased I_h and K⁺ channel currents in VTA DA neurons, and repeated infusion of I_h potentiator lamotrigine to the VTA of susceptible mice achieves antidepressant effects by inducing similar homeostatic plasticity. (A) Hyperpolarization-activated cation channel-mediated current (I_h) sample traces and statistic data for control (○), susceptible (■) and resilient ( ) mice. At −130 mV, F_(2,47) = 19.19, P < 0.0001; At −120 mV, F_(2,62) = 17.69, P < 0.001; n = 12–22 cells/8–10 mice per group. Post hoc at −130 mV analysis shows a significant increase in I_h in susceptible mice (t₃₂ = 2.65, P < 0.05) and, an even significantly larger I_h increase in the resilient subgroup (t₂₄ = 5.24, P < 0.001), compared to control. (B) Sample traces and statistic data of isolated K⁺ channel-mediated currents recorded from VTA DA neurons show resilient mice have significantly increased peak and sustained phases of K⁺ currents. At +90 mV, F_(2,58) = 15.129, P < 0.001; n = 14–23 cells/9–10 mice per group. Post hoc analysis shows a slight increase in peak K⁺ currents in susceptible mice (t₄₁ = 2.62, P < 0.05) and a larger increase in the resilient subgroup (t₃₆ = 5.25, P < 0.001), compared to control. (C) Susceptible mice display increased DA neuron excitability while resilient mice display a reduction, following incremental steps in current injections (50, 100, 150, and 200 pA) compared to controls (at 100 pA: F_(2,28) = 12.00, P < 0.001; at 150 pA F_(2,28) = 12.66, P < 0.001 and at 200 pA F_(2,25) = 8.86, P < 0.001). Post hoc analysis of susceptible and resilient compared to control for 100 and 150 and 200 pA currents at P < 0.05 (n = 8–12 cells/7–8 mice per group). (D and E) Experimental timeline and schematic. (F) 5 day 4 min daily bilateral infusions of lamotrigine (LTG, 0.1 μg) or vehicle into the VTA reversed social avoidance (t₁₈ = 5.79, P < 0.001; n = 10) and (G) sucrose preference (t₁₈ = 3.25, P < 0.01; n = 10). (H) Sample traces and statistic data of VTA DA neuron firing in susceptible mice following repeated infusion of vehicle compared to lamotrigine (t₃₂ = 4.10, P < 0.001; n = 17 cells/7–9 mice per group). (I) Sample traces and statistic data of I_h in susceptible mice following repeated infusion of vehicle (□) or lamotrigine (■) (at −130 mV: t₁₃ = 6.99, P < 0.0001; at −120 mV: t₁₃ = 5.88, P < 0.0001; n = 7–8 cells/6–8 mice per group). (J) Sample traces and statistic data of K⁺ currents in susceptible mice following repeated infusion of vehicle or lamotrigine: Peak (at +20 mV: t₁₉ = 5.03, P < 0.001; at +10 mV: t₁₉ = 5.92, P < 0.001) and sustained (at +20 mV: t₁₉ = 5.95, P < 0.001; at +10 mV: t₁₉ = 6.81, P < 0.001; n = 10–11 cells/7–9 mice per group). (K) Sample traces obtained at 100 pA current injection and statistic data of decreased excitability in susceptible mice infused with lamotrigine compared to vehicle (at 100 pA: t₁₅ = 6.41, P < 0.0001; at 150 pA: t₁₅ = 4.93, P < 0.001; at 200 pA: t₁₅ = 4.56, P < 0.001; n = 8–9 cells/7–9 mice per group). Error bars, ± s.e.m. * P < 0.05, ** P < 0.01, *** P < 0.001.