The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.

Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia-neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.

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Key pointsr Although learning can arise from few or even a single trial, synaptic plasticity is commonly assessed under prolonged activation. Here, we explored the existence of rapid responsiveness of synaptic plasticity at corticostriatal synapses in a major synaptic learning rule, spike-timing-dependent plasticity (STDP).r We found that spike-timing-dependent depression (tLTD) progressively disappears when the number of paired stimulations (below 50 pairings) is decreased whereas spike-timing-dependent potentiation (tLTP) displays a biphasic profile: tLTP is observed for 75-100 pairings, is absent for 25-50 pairings and re-emerges for 5-10 pairings. r Endocannabinoid-tLTP may represent a physiological mechanism operating during the rapid learning of new associative memories and behavioural rules characterizing the flexible behaviour of mammals or during the initial stages of habit learning.Abstract Synaptic plasticity, a main substrate for learning and memory, is commonly assessed with prolonged stimulations. Since learning can arise from few or even a single trial, synaptic strength is expected to adapt rapidly. However, whether synaptic plasticity occurs in response to limited event occurrences remains elusive. To answer this question, we investigated whether a low number of paired stimulations can induce plasticity in a major synaptic learning rule, spike-timing-dependent plasticity (STDP). It is known that 100 pairings induce bidirectional STDP, i.e. spike-timing-dependent potentiation (tLTP) and depression (tLTD) at most central synapses. In rodent striatum, we found that tLTD progressively disappears when the number of paired stimulations is decreased (below 50 pairings) whereas tLTP displays a biphasic profile: tLTP is observed for 75-100 pairings, absent for 25-50 pairings and re-emerges for 5-10 pairings. This tLTP, induced by very few pairings (ß5-10) depends on the endocannabinoid (eCB) system. This eCB-dependent tLTP (eCB-tLTP) involves postsynaptic endocannabinoid synthesis, requires paired activity (post-and presynaptic) and the activation of type-1 cannabinoid receptor (CB1R) and transient receptor potential vanilloid type-1 (TRPV1). eCB-tLTP occurs in both striatopallidal and striatonigral medium-sized spiny neurons (MSNs) and is dopamine dependent. Lastly, we show that eCB-LTP and eCB-LTD can be induced sequentially in the same neuron, depending on the cellular conditioning protocol. Thus, while endocannabinoids are usually thought simply to depress synaptic function, they also constitute a versatile system underlying bidirectional plasticity. Our results reveal a novel form of synaptic plasticity, eCB-tLTP, which may underlie rapid learning capabilities characterizing behavioural flexibility.