Blocking electrical synapses with mefloquine before nocturnal sleep impaired declarative memory retention and disrupted the coupling of sleep spindles to EEG slow oscillations, suggesting that electrical coupling enhances oscillatory coordination and thereby supports systems memory consolidation.
Key Findings
Results
Mefloquine administration before nocturnal sleep impaired the retention of word pairs learned before drug administration.
Participants were healthy young men administered mefloquine (250 mg p.o.) versus placebo before nocturnal sleep.
Word pairs were learned before drug administration, and retention was tested after the sleep interval.
The impairment was specific to the sleep condition, as mefloquine did not affect word-pair memory retention when administered before a consolidation interval of nocturnal wakefulness.
Memory retention was also unaffected when mefloquine was administered after rather than before sleep, establishing temporal specificity.
Results
Mefloquine disrupted the coupling of sleep spindles to EEG slow oscillations during nocturnal sleep.
Sleep spindle–slow oscillation coupling is considered a key neurophysiological mechanism of sleep-dependent memory consolidation.
The drug was administered at 250 mg p.o. before nocturnal sleep in healthy young men.
The disruption of spindle–slow oscillation coupling co-occurred with the impairment of declarative memory retention.
The authors conclude that electrical coupling enhances the oscillatory coordination between sleep spindles and slow oscillations.
Results
Electrical synapses specifically support sleep-dependent retention of verbal declarative memory, not wake-dependent consolidation.
In a control experiment, mefloquine was administered before a nocturnal wakefulness interval instead of sleep; word-pair retention was not affected.
In a second control experiment, mefloquine was administered after rather than before sleep; word-pair retention was again not affected.
These two control conditions together indicate that the drug effect on declarative memory is specific to the sleep consolidation window.
The authors describe this as suggesting that 'electrical synapses specifically support the sleep-dependent retention of verbal declarative memory.'
Results
Mefloquine enhanced the retention of sensorimotor memory assessed with a finger sequence tapping task, irrespective of sleep.
The finger sequence tapping task was used as a measure of sensorimotor (procedural) memory.
The enhancement occurred regardless of whether participants were in the sleep or wake condition.
This finding contrasts with the impairing effect of mefloquine on declarative memory, indicating memory-type-specific effects of electrical synapse blockade.
The authors note this effect was observed 'irrespective of sleep.'
Results
Mefloquine did not alter hippocampal sharp-wave/ripple activity in rats at doses of 20 and 40 mg/kg i.p.
Supplemental experiments were conducted in rats to test whether mefloquine affects hippocampal sharp-wave/ripple activity, a prominent mechanism of hippocampal memory replay.
Mefloquine was administered intraperitoneally at escalating doses of 20 mg/kg and 40 mg/kg.
Sharp-wave/ripple activity was not significantly altered at either dose.
This finding suggests that mefloquine's effects on memory consolidation are not mediated through disruption of hippocampal ripple-based replay mechanisms.
Discussion
The authors acknowledge that mefloquine effects beyond gap junction blockade cannot be fully excluded.
Mefloquine is an antimalarial drug primarily used to block electrical synapses (gap junctions), but it may have other pharmacological actions.
The authors explicitly state that 'mefloquine effects beyond gap junctions in the present experiments cannot be fully excluded.'
Despite this caveat, the authors conclude that electrical coupling plays a role in sleep-dependent memory consolidation.
This limitation is noted in the context of interpreting the causal role of electrical synapses.
What This Means
This research suggests that a type of direct neuron-to-neuron connection called electrical synapses (also known as gap junctions) plays an important role in how the brain consolidates memories during sleep. The researchers gave healthy young men a drug called mefloquine — an antimalarial that blocks these electrical connections — before they went to sleep and found that the men remembered fewer word pairs they had learned earlier that evening. The drug also disrupted a specific brain activity pattern during sleep: the coordination between two types of sleep-related brain waves called sleep spindles and slow oscillations, which are thought to be critical for transferring memories into long-term storage.
Importantly, the memory-impairing effect was specific to sleep. When participants took the drug before a period of nighttime wakefulness, or after they had already slept, their word-pair memory was unaffected. This suggests the drug interfered with something that happens specifically during sleep, rather than affecting memory encoding or general cognitive function. Interestingly, the drug had the opposite effect on a different type of memory — a finger-tapping motor skill task — where it actually improved performance regardless of sleep, pointing to different memory systems being affected differently by electrical synapse activity.
In additional rat experiments, the drug did not change another well-known memory mechanism in the brain (hippocampal sharp-wave ripples), suggesting the memory effects seen in humans were not due to disruption of that particular process. Overall, this research suggests that the brain's electrical synapse connections help coordinate the brain wave patterns during sleep that are necessary for locking in newly learned verbal and factual information, offering a new potential target for understanding and potentially treating memory disorders.
Feld G, Niethard N, Liu J, Gebhardt S, Kleist L, Brugger K, et al.. (2026). Electrical Synapses Contribute to Sleep-Dependent Declarative Memory Retention.. The European journal of neuroscience. https://doi.org/10.1111/ejn.70401