Metabolic and physiological mechanisms of PCP-induced psychosis

This took about ten years to work out! We started with the physiology (Maddy Kao’s thesis work published in Journal of Neuroscience). PCP discoordinates hippocampal discharge causing anti-cofiring cells to cofire amongst other forms of discoordination, but with almost effect on place cell firing fields. One might conclude the mechanism of action is ionotropic. However, clues from the LFP effects of BC1 RNA and Fmr1 genetic deletions made us explore metabotropic possibilities. A decade later, with almost every newcomer to the the lab contributing as they learned techniques, we find that PCP is acting through NR2A-containing NMDA receptors to dysregulate the translation molecular machinery.

Schematic of PCP’s proximal metabolic mechanism of action that dysregulates translation. These metabolic effects lead to cognitive control impairments and neuronal spike train discoordination within the hippocampus network without disturbing place fields. The activity vector correlation matrix shows that while CA1 ensemble activity patterns before PCP are self similar, they become uncorrelated under PCP for about 30 min, after which activity toggles between the PCP pattern and the pre-PCP pattern until about 40 min when it settles back to the pre-PCP state. Notice that the PCP ensemble discharge pattern was observed a few times before PCP was ever administered (red arrow heads). Is this what a hallucination would look like? In any case this demonstrates that the PCP did not induce the PCP-activity pattern, PCP only made the paper more likely.