HCN Channel Targets for Novel Antidepressant Treatment

Abstract

Major depressive disorder (MDD) is a chronic and potentially life threatening illness that carries a staggering global burden. Characterized by depressed mood, MDD is often difficult to diagnose and treat owing to heterogeneity of syndrome and complex etiology. Contemporary antidepressant treatments are based on improved monoamine-based formulations from serendipitous discoveries made > 60 years ago. Novel antidepressant treatments are necessary, as roughly half of patients using available antidepressants do not see long-term remission of depressive symptoms. Current development of treatment options focuses on generating efficacious antidepressants, identifying depression-related neural substrates, and better understanding the pathophysiological mechanisms of depression. Recent insight into the brain's mesocorticolimbic circuitry from animal models of depression underscores the importance of ionic mechanisms in neuronal homeostasis and dysregulation, and substantial evidence highlights a potential role for ion channels in mediating depression-related excitability changes. In particular, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential regulators of neuronal excitability. In this review, we describe seminal research on HCN channels in the prefrontal cortex and hippocampus in stress and depression-related behaviors, and highlight substantial evidence within the ventral tegmental area supporting the development of novel therapeutics targeting HCN channels in MDD. We argue that methods targeting the activity of reward-related brain areas have significant potential as superior treatments for depression.

Keywords: Depression; HCN channels; Ih current; antidepressants; neuronal excitability.

Fig. 1

Role of hyperpolarization-activated cyclic nucleotide-gated (HCN)1 in depression behaviors. (A) Global HCN knockout (KO) in the brain produces reduced behavioral despair in forced swim test and tail suspension test for all transgenic lines (HCN1^–/–, HCN2^–/–, and TRIP8b^–/–)[94]. (B) Selective dorsal hippocampal (HPC) reduction of HCN1 by short hairpin RNA (shRNA) HCN1 exhibited reduced behavioral despair in forced swim test, and, interestingly, anxiolytic effects in the open-field test and elevated plus maze test [108]. (C) Selective blockade of HCN channels in the prefrontal cortex (PFC) by ZD7288 or knockdown by shRNA HCN1.1 or shRNA HCN1.2 show improvements in working memory [113]. (D) Microinfusion of HCN blockers ZD7288 or DK-AH 269 into the ventral tegmental area (VTA) of susceptible/depressed mice reversed social avoidance behaviors [41]. Unexpectedly, chronic HCN channel potentiation by repeated lamotrigine administration or overexpression of HCN2 in dopamine neurons by herpes simplex virus–LS1L–HCN2 in susceptible animals induced resilience to depression behaviors [43]

Fig. 2

I_h current bidirectional modulation in the ventral tegmental area (VTA) of susceptible animals. (A, C) Microinfusion of hyperpolarization-activated cyclic nucleotide-gated (HCN) blockers ZD7288 or DK-AH269 into the VTA of susceptible animals rescues the social avoidance depression phenotype [41]. (B, D) HCN channel potentiation of susceptible animals by 5-day microinfusion of lamotrigine (LTG) induces homeostatic plasticity mechanisms in the VTA for resilience-like behavior and unsusceptible defeat stress phenotype. (E, F) Five-day LTG microinfusion produces larger I_h currents, which induces compensatory potassium currents to rescue social interaction behavior [43]