Microglia Activation, Herpes Infection, and NMDA Receptor Inhibition: Common Pathways to Psychosis?

Fig. 12.1

Inflammatory pathways to psychosis, adapted from Najjar et al. (2013). In the microglia/astroglia an M2 phenotype is favored, leading to a balance shift to the left in the microglia/astroglia metabolism in the figure: The cell produces more of the NMDA-R antagonist kynunerine is in comparison with the NMDA-R agonist quinolinic acid. Exposition to the glycoproteins of HSV induces MHCII class epitope expression, which also favors the left shift in the microglia/astroglia metabolism, this occurs by inhibition of IDO (indolamine deoxygenase) and KMO (kynunerine mono oxygenase) of the cell and thereby blocking of quinolinic acid formation. Net effect of the left shift in the metabolism of the microglia/astroglia is inhibition of the NMDA-R on glutamatergic (glutamate releasing) neurons. This leads to a reduction of the release of glutamate (crossed arrow on the above left) of the glutamatergic neuron. The postsynaptic GABAergic neurons then become less stimulated. Because GABA is the major inhibitory neurotransmitter of the brain (approx. 30 % of all neurotransmission is GABA ergic!) this leads to a state of disinhibition, which is assumed to be the cause of anti-NMDA psychosis. HSV antibodies may also act directly on the NMDA (NR-1) receptors and may induce psychosis in cases indistinguishable from “regular” anti-NMDA encephalitis. Also ketamine (and PCP) act directly against the NMDA-R (glycine site) and cause psychosis in 50 % of volunteers in a study by Vollenweider et al. (1997a). In contrast, hyperactivation of the NMDA-R by quinolinic acid is not associated with psychosis but with depression, negative symptoms of schizophrenia and neurodegenerative changes and is supposed to be due to an inflammatory response with Th1/M1 character

It is very interesting that the neurotoxic effects of herpes simplex encephalitis might be due overactivation of the NMDA receptor by the excitatory quinolinic acid (Reinhard 1998), and the more subtle behavioral changes by blockade of the NMDA receptor by the inhibitory kynurenic acid (Atlas et al. 2013).

All these clinical and pre-clinical observations on the etiology of immune or pharmacologically mediated psychoses suggest that the final common pathway to psychosis might be NMDA receptor antagonism. Drugs (ketamine), immune/neurotransmitter signaling molecules (kynurenic acid) and specific (NMDA) antibodies can all produce the classic phenotype of a paranoid psychosis with predominant positive symptoms (hallucinations and delusions).

Blockade of NMDA receptors is hypothesized to cause psychosis by the following mechanism. Glutamate is an excitatory neurotransmitter released from pyramidal cells. Glutamate is released predominantly to interneurons that possess the NMDA receptor and release the inhibitory neurotransmitter GABA. By blocking the effects of glutamate on the NMDA receptor of interneurons, these inhibitory neurons deactivate. This leads to less release of the inhibitory neurotransmitter GABA and consequent disinhibition/activation of cortical circuitry (Olney et al. 1991), which may be responsible for the psychotic phenomena.

Conclusion

It is very difficult to delineate etiology in mental disorders. The brain is not easy to approach for molecular tests. However, making use of unique molecular probes for PET imaging, we might come closer to the understanding of which external factors might be triggers for transition from perfect health to severely debilitating diseases such as schizophrenia. Psychosis of different etiology might share the pathogenesis in the common mechanism of the inhibition of NMDA signaling. Psychosis could therefore be mediated by NMDA blockade as a result of environmental factors such as social stress, hallucinatory drug use, auto-immune disease, or neurotropic viruses.

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