Acute DOI exposure drives cortical hyperexcitability and functional network remodeling

Area of Science:

• Neuroscience
• Pharmacology
• Computational Biology

Background:

• Serotonergic psychoplastogens induce lasting brain changes.
• The effects of 5-HT2A agonist DOI on neural network dynamics are not fully understood.

Purpose of the Study:

• To investigate how acute 2,5-dimethoxy-4-iodoamphetamine (DOI) exposure impacts population activity and functional connectivity in rat cortical cultures.
• To explore the role of 5-HT2A receptors in DOI-induced network alterations.

Main Methods:

• Primary rat cortical cultures were recorded using microelectrode arrays (MEAs) before and after DOI administration.
• Network activity was analyzed by measuring spikes, bursts, and functional connectivity (Pearson cross-correlation, spike-time tiling coefficient).
• A ketanserin + DOI group was used to assess 5-HT2A receptor involvement.

Main Results:

• DOI exposure increased mean firing rate and accelerated burst timing in cortical cultures.
• Functional network analysis revealed a shift towards shorter characteristic path length, indicating increased integration.
• Ketanserin partially blocked DOI's effects, reducing population bursting but preserving path-length shortening, suggesting a complex interaction with 5-HT2A receptors.

Conclusions:

• Acute DOI exposure induces a hyperexcitable state in cortical networks with altered functional dynamics.
• MEA recordings offer a method to link psychoplastogen effects to systems-level circuit outcomes.
• These findings are relevant for understanding the mechanisms of therapeutic plasticity induced by psychedelics.