A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus

Abstract

The subgranular zone (SGZ) of dentate gyrus (DG) is one of the few regions in which neurogenesis is maintained throughout adulthood. It is believed that newborn neurons in this region encode temporal information about partially overlapping contextual memories. The 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring compound capable of inducing a powerful psychedelic state. Recently, it has been suggested that DMT analogs may be used in the treatment of mood disorders. Due to the strong link between altered neurogenesis and mood disorders, we tested whether 5-MeO-DMT is capable of increasing DG cell proliferation. We show that a single intracerebroventricular (ICV) injection of 5-MeO-DMT increases the number of Bromodeoxyuridine (BrdU+) cells in adult mice DG. Moreover, using a transgenic animal expressing tamoxifen-dependent Cre recombinase under doublecortin promoter, we found that 5 Meo-DMT treated mice had a higher number of newborn DG Granule cells (GC). We also showed that these DG GC have more complex dendritic morphology after 5-MeO-DMT. Lastly, newborn GC treated with 5-MeO-DMT, display shorter afterhyperpolarization (AHP) potentials and higher action potential (AP) threshold compared. Our findings show that 5-MeO-DMT affects neurogenesis and this effect may contribute to the known antidepressant properties of DMT-derived compounds.

Keywords: 5-MeO-DMT; adult neurogenesis; dentate gyrus granule cells; patch clamp; psychedelics.

Figure 1

Single dose of5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) increases cell proliferation within the dentate gyrus (DG) of adult mice. (A) Photomicrography showing representative hippocampal sections Bromodeoxyuridine (BrdU+) cells in green and hoechst 33342 in blue. (B) Average number of BrdU+ cells in the adult mice ventral DG. (C) Mean number of cells per clusters. (D) Mean number of clusters in each group. *p = 0.0029, **p = 0.0002.

Figure 2

Single dose of 5-MeO-DMT increase the number of new DG granule cells (GC) 21 days after injection. (A) Photomicrography showing representative hippocampal sections (DCX::tdTom+ cells in red and hoechst 33342 in blue). (B) Average number of DCX::tdTom+ cells per group. *p = 0.0006.

Figure 3

5-Meo-DMT injection alters afterhyperpolarization (AHP) duration and action potential (AP) threshold in immature hippocampus GC. (A) Animals received a dose of 100 μg of 5-MeO-DMT, followed by 100 μg/g of tamoxifen i.p. diluted in sesame oil 3 days after, daily for 3 days to allow cre recombination. Experiments were performed on day 21. (B) Photomicrography of a recorded tdTomato+ cells from control and 5-MeO-DMT-treated mouse. (C) Membrane potential changes in response to current steps, the black line denotes the trace in which the first AP was elicited, red dotted line denote AP threshold for that step. (D) Mean AP threshold. (E) Mean AHP duration. *p = 0.0216, **p = 0.0062.

Figure 4

Young GC in 5-MeO-DMT-treated mice show a greater capacity for high frequency firing. (A) Membrane potential recording in response to a current ramp. (B) Linear regressions (ramp current vs. instantaneous AP frequency). (C) Average slopes (ramp current vs. instantaneous AP frequency relationship). **p = 0.0036.

Figure 5

Young GC in 5-MeO-DMT-treated show a higher frequency of spontaneous excitatory postsynaptic potentials. (A) Examples of detectedspontaneous excitatory postsynaptic currents (sEPSCs; in 2 min recordings) cells from saline- and 5-MeO-DMT-treated mice. (B) Mean absolute sEPSC amplitude for saline- and 5-MeO-DMT-treated mice. *p = 0.03. (C) Average slopes (ramp current vs. instantaneous AP frequency relationship). **p = 0.001.

Figure 6

Single dose of 5-MeO-DMT increases dendritic complexity in young DG GC. (A) Sample image showing a tdTomato+ (CreER^T2/tdTom^lox/lox mouse) granule cell with visible dendritic processes. (B) Vectorial reconstruction of tdTomato+ granule cell. (C) Mean number of branch tips of GC across treatments. (D) Sholl analysis comparing the dendritic complexity between two treatments with increasing radial distance from soma. *p = 0.0001, **p < 0.05.