Schizophrenia and Psychosis: Glutamate System

Introduction to Glutamate and NMDA Hypofunction

• Negative symptoms and deficient states in schizophrenia linked to underactivity of mesocortical dopamine projections.
• Theory: Neurodevelopmental abnormalities in NMDA glutamate system contribute to psychosis and schizophrenia.

Glutamate Theory of Psychosis

• NMDA receptors are hypofunctional at synapses in the prefrontal cortex.
• Disruptions can be due to:
  • Neurodevelopmental abnormalities (schizophrenia)
  • Neurodegenerative abnormalities (Alzheimer's, dementias)
  • NMDA receptor blocking actions of drugs (ketamine, PCP)

Understanding Glutamate

• Amino acid acting as neurotransmitter; major workhorse of the brain.
• Synthesized in the brain from glucose; reuptake and replenishment by glial cells.
• Glutamate interacts with receptors via synaptic vesicles.
• Transported into neighboring glia by excitatory amino acid transporter (EAAT).

Glutamate Receptors and Pathways

• Three prominent receptors: NMDA, AMPA, and kainate.
• NMDA receptors allow entry of calcium; play a role in synaptic plasticity.
• Glutamate pathways relevant to psychopharmacology:
  • Cortico-brainstem, corticostriatal, hippocampal-striatal, thalamocortical, corticothalamic.
  • Direct and indirect corticocortical pathways.

Role of Glycine and D-Serine

• Glycine and D-serine act as co-transmitters for NMDA receptors.
• Glycine sourced from glia, not stored in vesicles; D-serine may be stored.
• D-serine synthesized from L-serine by D-serine racemase.

Dysfunction in Schizophrenia

• Faulty NMDA synapses lead to excess dopamine in mesolimbic pathway.
• GABA interneuron dysfunction due to deficits in enzyme GAD67.
• Parvalbumin-containing GABA interneurons implicated in schizophrenia.

Links to Dopamine Hypothesis

• Excess dopamine in mesolimbic pathway linked to positive symptoms.
• Deficient dopamine in mesocortical pathway linked to negative symptoms.
• NMDA hypoactivity indirectly affects dopamine levels through GABA interneurons.

Conclusion

• Glutamate dysfunction at specific synapses may cause psychosis.
• Neurodevelopmental changes, neurodegenerative diseases, and certain drugs contribute to hypofunction.
• Understanding glutamate pathways critical to understanding psychosis and potential treatments.