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.

The potential role of the HCN1 ion channel and BDNF-mTOR signaling pathways and synaptic transmission in the alleviation of PTSD

“…In this study, we only detected the lower level of BDNF in the Hip. Another possibility may be that when chronic stress and consequent HCN channel dysfunction desynchronize cortical networks, prefrontal control over behavior, emotion, and cognition could be affected as well 7 . In other words, different physiological functions and abnormal behavior phenotypes might be evoked consistently.…”

“…HCN1 appears to be the most predominant isoform expressed in the hippocampus (Hip), prefrontal cortex (PFC), neocortex, and cerebellar cortex. It can be regulated by the nucleotide cyclic adenosine 3',5'-monophosphate (cAMP) and ZD7288 7 . Several studies have pointed out that selective dorsal Hip reduction of HCN1 by short hairpin RNA (shRNA) exhibits reduced behavioral despair in the forced swim test (FST) and anxiolytic effects in the open-field test (OFT) and elevated plus maze test (EPMT) 8 .…”

Antidepressant and pro-motivational effects of repeated lamotrigine treatment in a rat model of depressive symptoms

“…Moreover, chemogenetic activation of VTA dopaminergic neurons results in an increased responding for sucrose in a PR schedule of reinforcement, that is, it enhances incentive motivation [60] . VTA dopaminergic neurons that project to the NAcS exhibit a large hyperpolarization-activated inward current, I h , that modulates their electrophysiological properties and firing rate [61] . This current that modulates VTA firing activity seems to be crucial for the formation of cue-reward association and motivated behaviors [ 27 , 61 ].…”

The structure and function of TRIP8b, an auxiliary subunit of hyperpolarization-activated cyclic-nucleotide gated channels

“…Recent work in several brain regions has implicated HCN channels in MDD (reviewed elsewhere [67]). In many regions outside the hippocampus, animal models pertinent to MDD have observed that loss of I h is associated with more depression-like behavior [68][69][70].…”