MDMA MODULATES HIPPOCAMPAL NETWORK ACTIVITY

MDMA is a psychoactive drug that elicits its effect by producing monoaminergic surge, particularly of serotonin. Hippocampus exhibits various serotonergic receptor subtypes highlighting the importance of serotonergic tone in this region. We asked whether and how MDMA modulates or reshapes hippocampal network activity. In the current work, we have applied in-vivo and in-vitro electrophysiological approaches to decipher the impact of MDMA on hippocampus. We performed high density Neuropixels recordings in head-fixed mice in response to local MDMA injection in the CA1 hippocampal region and found a significant increase in ripple occurance. Similarly, we found an increased ripple incidence in hippocampal slices after washing in with MDMA. Next, we used fenfluramine, a serotonin releasing drug, which also resulted in a robust increase in ripple activity. To unravel the mechanism of action of ripple increase, we used ketanserine, a 5HT2R antagonist and found an abolishment of ripple increase. Taken together, we found that serotonin increases hippocampal ripple activity which is mediated by 5HT2R signalling. Increased ripple incidence after MDMA may signify enhanced reactivation required for reconfiguring the memory engrams. MDMA has gained a greater deal of attention as it has received breakthrough drug designation by FDA in treatment of psychiatric disorders like PTSD. The current work opens up new avenues about the mechanism of action of MDMA at circuit/network level which may help in advancing the understanding of its potential therapeutic role.