Opposing forces shape our everyday lives — for instance, stimuli can encourage us to move or stop, and events can make us happy or sad. Accordingly, our brains are designed with ‘yin–yang’ systems that guide our actions and influence our feelings. Neurons in the brain’s mesolimbic system promote reward-seeking behaviour and help to process information about actions that result in pleasurable outcomes1–3. By contrast, neurons in the lateral habenula (LHb) encode information related to noxious outcomes and suppress reward-seeking4–6. Unbalancing these opposing systems might therefore affect our behaviour. Indeed, emerging evidence7 suggests that LHb hyperactivity contributes to mood disorders such as major depression. Two papers8,9 in Nature now shed light on the mechanisms that underlie LHb hyperactivity, and on how the antidepressant drug ketamine modulates this state.
In the first paper, Yang and colleagues8 assessed the firing activity of LHb neurons in two rat models of depression. Neuronal firing involves depolarization of the electrical potential across the cell membrane (in a resting state, the inside of the cell is negatively charged relative to the extracellular space around it). Hyperpolarization, in which the cell interior becomes more negative than normal, is typically associated with neuronal inhibition.
By studying brain slices ex vivo, Yang and co-workers showed that LHb neurons were more likely to fire in a pattern of rapid bursts in the ‘depressed’ rats than in control animals. They also observed that, when the LHb neurons were hyperpolarized, this increased the likelihood that these cells would fire in bursts rather than steady volleys. The researchers went on to show that they could increase depression-like behaviours in rats using a genetic manipulation to drive hyperpolarization, and so burst firing, in LHb neurons.
Next, the group investigated the signals that regulate this burst firing. In other brain regions10, burst firing is controlled by N-methyl-d-aspartate receptors (NMDARs) — membrane-spanning channel proteins whose activation leads to an influx of positively charged calcium ions into neurons, resulting in depolarization and neuronal firing. Yang and colleagues found that burst firing of LHb neurons required the activity of NMDARs and of another class of protein, T-type voltage-sensitive calcium channels (T-VSCCs).
Could inhibition of NMDARs prevent bursting? Ketamine is an NMDAR inhibitor and a promising, rapid-acting antidepressant in humans (taking effect in as little as 30 minutes)11 that is currently in clinical trials for the treatment of major depressive disorder with imminent risk of suicide. The mechanisms by which ketamine acts have been a puzzle to scientists. Strikingly, Yang et al. found that local infusion of ketamine into the LHb elicited antidepressant-like responses in depression-prone rats. These findings suggest that the therapeutic actions of ketamine might relate, at least in part, to its ability to block burst firing in the LHb.
In the second paper, Cui et al.9 turned their attention to the mechanisms by which LHb neurons become skewed to firing in burst mode during depression. The authors performed a large-scale analysis of differentially expressed proteins in the LHb. This revealed that the expression of Kir4.1, a component of potassium-ion (K+) channels, was increased in the LHb of depression-prone rats compared with that of controls.
Kir4.1 is expressed in astrocytes, cells that interact with neurons to influence their activity state12 (although the functional relevance of such interactions is still being defined). The researchers showed that overexpression of Kir4.1 in LHb astrocytes increased the burst firing of local neurons and precipitated depression-like behaviours in mice. Conversely, reducing Kir4.1 expression in depression-prone rats reduced the burst firing of LHb neurons, and attenuated the animals’ depression-like behaviours.
How do Kir4.1-containing channels in astrocytes regulate the activity of neurons? Neurons can pump K+ from their cytoplasm into the extracellular space to cause hyperpolarization. Cui et al. provide evidence that astrocytic K+ channels in the LHb help to clear away extracellular K+. This facilitates the ability of LHb neurons to enter a hyperpolarized state, and hence to fire in bursts (Fig. 1). Future studies will be required to understand whether LHb astrocytes interact with neurons in other ways to influence their patterns of activity.
Together, these two papers provide crucial insights into a depression-associated pattern of cell firing in the LHb and its regulation by ketamine. However, exactly why burst firing of LHb neurons increases depression-like behaviours in rodents remains unclear. One potential explanation, put forward by Yang et al., is the inhibitory influence that LHb neurons exert over reward-associated dopamine neurons in the mesolimbic system and mood-associated serotonin neurons in the midbrain. Perhaps burst firing of LHb neurons alters the activity of these downstream neurotransmitter systems in a manner that reduces their positive effects on mood, thereby increasing vulnerability to depression. Testing this possibility, and other potential mechanisms, will require further experimentation. The potential involvement of subpopulations of dopamine and serotonin neurons that encode aversion-relevant stimuli must also be considered13.
The current studies have several therapeutic implications. First, Cui and colleagues’ data show that astrocytes might have a key role in regulating a brain system involved in mood and motivation. Previous studies linking astrocyte function to disease states have focused mostly on neurodegenerative and developmental disorders14,15, but the current papers suggest that modulating the activity of these cells might be a way to treat psychiatric disorders.
Second, Yang et al. showed that a T-VSCC blocker delivered directly into the LHb had antidepressant-like effects, similar to those of ketamine. This raises the exciting possibility that T-VSCC blockers, or other compounds that suppress LHb burst firing, could be effective antidepressants.
Finally, the papers shed light on the possible mechanisms by which ketamine elicits rapid antidepressant effects in humans. Ketamine and its metabolites stimulate the formation of synaptic connections between neurons in the brain16–18, a process that is thought to be important for the drug’s therapeutic effects. The findings suggest that another property of the drug — its ability to inhibit burst firing in a brain region implicated in aversion and negative mood — also contributes to its efficacy and explains its rapid onset of action. This knowledge might facilitate the development of next-generation ketamine-related antidepressants that specifically target LHb activity and that might eliminate two major side effects of ketamine and other NMDAR blockers: their abuse potential and the induction of a transient, schizophrenia-like, psychotic state.
Nature 554, 304-305 (2018)
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