Enhanced endocannabinoid signaling boosts signal propagation through the hippocampal trisynaptic circuit and facilitates safety learning

Anxiety disorders like post-traumatic stress disorder or obsessive-compulsive disorder are frequently diagnosed and often occur in combination with other mental illnesses. Exposure-based therapies along with medication are widely used as treatment for most of these brain based diseases. The frequently used benzodiazepines are usually considered second-line due their impact on amnestic functions. In contrast, substances targeting the endocannabinoid system were found to be effective anxiolytics without disadvantages on memory function. However, the changes in millisecond-scale brain circuit dynamics that might underlie their therapeutic actions remain elusive. Here, enabled by a recently developed voltage-sensitive dye imaging assay in mouse brain slices, we compared the impact of diazepam and the cannabinoid neurotransmission enhancer AM404 on neuronal activity propagations through the entire trisynaptic circuitry of the hippocampus (“HTC”: perforant path dentate gyrus-area CA3-CA1 output subfield). Bath applied diazepam (1 µM) depressed activity propagations (“HTC-Waves”), which coincided with impaired safety learning. In contrast, bath applied AM404 (10 µM) boosted HTC-Waves in CA regions, and facilitated safety learning. These effects were absent in D1CB1-KO mice. Collectively, we demonstrate opposing effects of two anxiolytic drugs on the hippocampal network that might underlie their inverse impact on amnestic functions during exposition-based therapies.