Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology

Area of Science:

• Neuroscience
• Psychiatry
• Molecular Biology

Background:

• The hippocampus plays a crucial role in schizophrenia's psychotic symptoms.
• Elevated basal hippocampal activity and reduced task-related activation are observed in psychosis.

Purpose of the Study:

• To investigate the molecular pathology in the hippocampus underlying psychotic symptoms.
• To explore the role of repressor element-1 silencing transcription factor (REST) in schizophrenia.

Main Methods:

• Positron emission tomography (PET) and magnetic resonance (MR) perfusion techniques to measure hippocampal activity.
• Analysis of human psychosis tissue for molecular changes, including NMDA receptor subunits and postsynaptic density protein-95 (PSD-95).

Main Results:

• Increased GluN2B-containing NMDA receptors, PSD-95, and dendritic spines in the hippocampal CA3 subfield in psychosis.
• Evidence suggests a reduction in the gene repressor REST's influence, impacting NMDA receptor maturation.

Conclusions:

• Hippocampal CA3 molecular alterations in psychosis may lead to hyperactivity and false memory formation.
• Reduced REST function could be a key factor in the pathophysiology of schizophrenia-associated psychosis.