Increased Excitability of GABAergic Interneurons by the Psychedelic N,N-Dimethyltryptamine (N,N-DMT)
N,N-Dimethyltryptamine; GABAergic interneurons;
balance; Single-cell electrophysiology; Calcium imaging; Hippocampus.
Inhibition is crucial for maintaining excitatory/inhibitory (E/I) balance; disruptions in this balance are associated with neurodevelopmental and neuropsychiatric disorders. Psychedelics have emerged as promising candidates for addressing many neuropathophysiologies characterized by E/I imbalance.
N,N-Dimethyltryptamine (DMT), in particular, induces changes from cellular to network levels, an effect that could be attributed to its modulation of excitatory/inhibitory balance by enhancing neuronal inhibition. Despite this, the specific role of GABAergic interneurons in mediating DMT's effects on circuits has not been systematically investigated.
Here, we hypothesize that DMT potentiates GABAergic inhibition onto excitatory neurons by enhancing interneurons’ excitability in the hippocampus.
To test this hypothesis, we will employ a dual approach:
(i) single-cell electrophysiology (whole-cell voltage-clamp) to measure inhibitory postsynaptic currents (IPSCs) in murine hippocampal slices, and
(ii) calcium imaging of hippocampal neurons in freely behaving mice utilizing the genetically encoded calcium indicator jGCaMP7f and a miniaturized microscope (miniscope V3).
By combining in vitro and in vivo approaches, this project aims to determine whether DMT enhances inhibitory neurotransmission, potentially revealing a novel mechanism underlying its therapeutic effects.