ENDOCANNABINOIDS SIGNALING REGULATES SHARP-WAVE RIPPLES FUNCTION ACROSS LEARNING

Learning and memory critically depend on hippocampal network dynamics. Sharp-wave ripples (SPW-Rs) are brief hippocampal network events essential for memory consolidation, characterized by highly synchronous neuronal firing and increased population spiking. Endocannabinoids (eCBs) are released during periods of elevated neuronal activity and act primarily through type-1 cannabinoid receptors to regulate presynaptic neurotransmitter release, particularly at inhibitory synapses formed by CCK/Id2 interneurons. Here, we hypothesize that elevated neuronal activity associated with SPW-Rs constitutes a key trigger for endocannabinoid release in CA1, positioning eCB signaling as a regulator of SPW-R–induced plasticity. To test this, we chronically implanted high-density silicon probes coupled with optical fibers in CA1, enabling simultaneous recording of extracellular neuronal activity and eCB dynamics using the GRABeCB3.0 sensor expressed in hippocampal neurons. Mice were recorded over a two-week period, encompassing sleep sessions and learning of a rewarded spatial alternation task. Notably, eCB levels increased during SPW-R events and were further modulated in a learning-dependent manner. Consistent with their prominent expression of CB1 receptors, increased eCB signaling was associated with a reduction in CCK/Id2–pyramidal cell coupling. In turn, SPW-Rs with higher eCB levels were accompanied by a modest increase in the firing rates of superficial pyramidal cells. Together, these results reveal a ripple-associated endocannabinoid mechanism that selectively modulates inhibitory control onto pyramidal neurons during learning. Future experiments will knock down CB1 receptors in CCK/Id2 interneurons to directly test their causal role in inhibitory circuit plasticity.