Abstract
Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K+) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K+ channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms.
Highlights
Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment
It is known that these XE-991-sensitive currents include KCNQ2/3 heterodimers that exhibit an 11-fold larger current compared with KCNQ2 or KCNQ3 homomers[12,16]
In vitro slice recordings revealed that KCNQ3-expressing neurons had significantly lower ventral tegmental area (VTA) DA neuron firing activity (Fig. 1i) as compared with the eYFP control group
Summary
Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms. In vivo intra-VTA blockade of KCNQ channels by XE-991, a KCNQ blocker, in the mice previously classified as resilient exhibited social avoidance behaviours similar to susceptible animals[14,15]. Together, these data indicate that KCNQ may be involved in maintaining the stable resilient phenotype and that the normal firing status of VTA DA neurons is dependent on XE-991 sensitive currents. The increased KCNQ3 seen in resilient mice[1] may play a functional role in stabilizing VTA neuronal activity at the cellular level[17,18]
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