Synaptic potentiation mediated by L-type voltage-dependent calcium channels mediates the antidepressive effects of lateral habenula stimulation.

Although deep-brain stimulation (DBS) of the lateral habenula (LHb) has been successfully applied to treatment-resistant depression for years, the mechanism is still unclear. Previous researches have demonstrated that LHb-DBS elevates brain monoamine neurotransmitters. However, these changes do not account for the treatment efficacy on treatment-resistant depression, or the rapid behavioral effects in rats; the evidence suggests that altered synaptic potentiation may contribute to the treatment effects. We applied LHb-DBS in a rat model of learned helplessness (LH) and analyzed mammalian target of rapamycin (mTOR) phosphorylation. We also assessed related electrophysiological changes after LHb-DBS in vitro. LHb-DBS reversed depression-like behaviors in sucrose preference and forced swim tests in rats with LH. Additionally, mTOR phosphorylation significantly increased and field population excitatory postsynaptic potentials increased in the hippocampus. These effects were blocked by the L-type voltage-dependent calcium channel (L-VDCC) antagonist, nifedipine. Furthermore, in vitro LHb-DBS increased both the frequency and width of spontaneous spikes generated by CA1 pyramidal neurons, which contribute to Ca2+ influx through L-VDCC. Our findings suggest that L-VDCC-mediated synaptic potentiation underlies the antidepressant effects of LHb-DBS, and suggest that astrocytic regulation of Ca2+ influx and associated synaptic changes maybe novel targets for developing antidepressant treatments.