PerspectiveNeuroscience

HCN1 Channels: A New Therapeutic Target for Depressive Disorders?

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Science Signaling  02 Oct 2012:
Vol. 5, Issue 244, pp. pe44
DOI: 10.1126/scisignal.2003593

Abstract

The hyperpolarization-activated cyclic nucleotide-gated channels are cation channels that are activated by hyperpolarizing potentials. These channels are concentrated in cortical and hippocampal pyramidal cell dendrites, where they play an important role in determining synaptic input integration and thus neuronal output. These channels have thus been suggested to be involved in physiological processes such as cognition as well as pathophysiological states such as epilepsy. Recent evidence suggests that these channels may also be therapeutic targets for treatment of depressive disorders.

Depression is a psychiatric illness that affects approximately 17% of the population (1). Although the underlying molecular and cellular mechanisms remain to be fully evaluated, monoamine neurotransmitters, glutamatergic signaling, and various growth factors have been implicated in depression (Fig. 1). A deficit in monoamine [noradrenaline and 5-hydroxytryptamine (5-HT, also known as serotonin)] neurotransmitter release may be one of the causes (1, 2). Indeed, many currently available antidepressants enhance noradrenaline, or serotonin concentrations, or both, in the synaptic cleft. In addition, alterations in glutamate concentrations or glutamate receptor activity, as well as the abundance of brain-derived neurotrophic factor (BDNF), in the hippocampus may be important factors (2, 3). Consistent with a key role for BDNF, patients with depression have lower serum concentrations of BDNF (2).

Fig. 1

Cellular mechanisms leading to antidepressant effects. The illustration depicts the various cellular pathways that lead to enhanced BDNF synthesis in the hippocampus. Antidepressants increase the amount of monoamines, such as 5-hydroxytryptamine (5-HT) and noradrenaline (NA), in the synaptic cleft. These act on their respective receptors (R) to stimulate cAMP and protein kinase A (PKA), resulting in phosphorylation of cAMP response element–binding (CREB), a transcription factor, and greater BDNF production. Pharmacological inhibition of N-methyl-d-aspartate (NMDA) receptors or reduced activity of HCN channels enhances BDNF production. Reduced activity of HCN channels also stimulates the kinase mTOR. The molecular mechanisms by which reduced HCN channel function augments BDNF synthesis and mTOR phosphorylation remains to be resolved.

CREDIT: Y. HAMMOND/SCIENCE SIGNALING

The anesthetic ketamine is an antagonist of a specific subtype of glutamate receptors (3) and of hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels (4). However, doses lower than those required for anesthesia have antidepressant effects and, in mouse models, increase the abundance of BDNF (5). Although most of the effects of ketamine have been ascribed to its function as a glutamate receptor antagonist, because ketamine is also an HCN1 channel antagonist (4), it is possible that inhibition of HCN1 channels could contribute to or be responsible for its antidepressant effects. Kim et al. (6) provide evidence to support this notion.

HCN channels are cation channels that open at membrane voltages more negative than –40 mV (7). Four subunits (HCN1 to HCN4) have been identified (8, 9). The predominant forms in the hippocampus and cortex are HCN1 and HCN2 (10). The channels formed by heteromeric or homomeric complexes of these subunits are mainly located in pyramidal cell dendrites, although they can also be present in certain interneurons, as well as neuronal axons and synaptic terminals (1013). In dendrites, these channels are open at rest and are involved in maintaining the resting membrane potential and membrane resistance. Pharmacological inhibition of the channels or genetic ablation of HCN1 results in a hyperpolarized resting membrane potential and increased input resistance (14, 15). Consequentially, reduction in HCN channel function results in an increase in the summation of synaptic inputs on distal dendrites, which increases the propensity for neurons to fire action potentials (16). Long-term potentiation at distal dendrites is also enhanced. Moreover, mice in which HCN1 ablation is restricted to the forebrain have augmented hippocampal-dependent learning (15).

Tetratricopeptide repeat–containing Rab8b interacting protein (TRIP8b) promotes HCN1 trafficking and appearance at the plasma membrane in dendrites (17). TRIP8b-null mice displayed resistance to behavioral despair in multiple animal models of depression (18). These effects were likely due to reduced abundance of HCN subunits because similar effects were also observed with HCN1- or HCN2-null mice. Intriguingly, the suppression of depression-like behaviors was greater in HCN1- or HCN2-null mice than in the TRIP8b-null mice (18). Because HCN1 and HCN2 were lacking in all brain regions, it was unclear whether hippocampal or cortical or channels in both regions were important for the antidepressant effects.

Kim et al. reduced the abundance and function of HCN1 selectively in dorsal hippocampal neurons by injecting lentiviral HCN1–short hairpin RNA (shRNA) constructs into this brain region (6). This resulted in a 50% decrease in HCN1 abundance within 28 days in ~30% of neurons. The reduction in HCN1 abundance persisted for up to 6 months. The abundance of HCN2 was unaffected. As expected with a reduction in HCN1 channel function (19), neurons infected with lentiviral HCN1-shRNA constructs had more hyperpolarized resting membrane potentials and increased input resistance as compared with those of controls. Hence, a train of synaptic inputs summated more at a given potential in those neurons expressing the HCN1-shRNA construct. To determine whether these rodents had altered behavioral despair, they subjected the rodents in which HCN1 was knocked down and controls to the forced swim test. In this stressful environment, normal animals exhibit active activity (swimming and climbing), whereas those animals that are depressed exhibit a more passive, less mobile response (20). Remarkably, even though HCN1 was only partially reduced in a small percentage of neurons, the animals infused with lentivirus HCN1-shRNA constructs in the dorsal hippocampus displayed significantly greater activity than the controls. These results were similar to those obtained with rodents treated with the antidepressants fluoxetine, a selective serotonin reuptake inhibitor, or ketamine. Similar to diazepam-treated animals, the animals with targeted knockdown of HCN1 exhibited less anxiety in the open field and elevated plus maze tests. Interestingly, the abundance of BDNF and the phosphorylated form of the kinase mammalian target of rapamycin (mTOR) was increased in animals in which HCN1 was partially reduced (Fig. 1).

The findings of Kim et al. (6) have several profound implications. They indicate that modifications in neuronal activity within the dorsal hippocampus are likely to play an important role in the induction of depressive disorders. They also indicate that changes in the excitability in a small population of neurons is sufficient to cause a widespread alteration in neural network activity because even though only 30% of the dorsal hippocampal neurons were infected with the lentivirus HCN1-shRNA construct, voltage-sensitive dye imaging showed that activity within large hippocampal areas was modulated. Last, their results suggest that HCN1 channels may be a novel therapeutic target for depression.

Many of the currently available antidepressants take a long time to exert their effects (1, 2), and thus, other fast-acting treatments would be beneficial. Because only a partial reduction of HCN1 channel function is sufficient to induce behavioral effects, at least in rodents, potential side effects such as seizure susceptibility (19) and deficits in motor coordination (21) may be limited, and the antidepressant effects may be relatively rapid.

Finding that inhibition of HCN channels leads to antidepressant-like effects and enhances the abundance BDNF and phosphorylated mTOR raises some interesting and exciting questions. What might the cellular mechanism (or mechanisms) be by which a reduction in HCN channel function leads to increased BDNF synthesis and activation of mTOR (Fig. 1)? Moreover, HCN channels are modulated by various intracellular messengers, such as adenosine 3ʹ,5ʹ-monophosphate (cAMP) (7), which are produced downstream of receptors activated by monoamines, such as noradrenaline. Alterations in glutamate release as has been suggested to occur during depression (1) can also cause changes in HCN channel abundance and function (22, 23). Therefore, is the function and expression or abundance of HCN subunits in the hippocampus altered during depression? The answers to these questions are likely to yield a better understanding of the molecular and cellular mechanism (or mechanisms) leading to the pathophysiology of depression and perhaps result in better therapies.

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