Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
254—Schizophrenia: Molecular and Cellular Mechanisms
Sunday, November 10, 2013, 1:00 pm - 5:00 pm
254.02: Evidence of hippocampal ca3-specific nmda receptor pathology in psychosis in schizophrenia
Location: Halls B-H
*C. A. TAMMINGA1, W. LI2, J. PEREZ3, B. POTTS4, C. MEYER4, S. ARIAGNO4, S. GHOSE2; 1Univ. Texas Southwestern Med. Ctr., Dallas, TX; 2Psychiatry, 3Psych, 4UT Southwestern Med. Ctr., Dallas, TX
Abstract Body: Schizophrenia has no known cellular or molecular pathophysiology, thus putting it at great disadvantage with respect to diagnostic considerations and therapeutic drug development. The most florid and unusual of its clinical dimensions is psychosis. In psychosis, the brain generates false, persistent and unpleasant perceptions (hallucinations) and false beliefs (delusions) much like psychotic memories. We have proposed a learning and memory model of psychosis, which is based on early evidence of increased perfusion in schizophrenia hippocampus, along with reduced glutamate signaling in dentate gyrus (AmJPsych 167:1178, 2010); therefore, we have been testing CA3 not only for evidence of increased in vivo function but also for in vitro tissue correlates of increased synaptic strength. The increase in CA3 function plausibly could generate vulnerability for mistakes of association and could mediate their encoding as false memories, even those with psychotic content. To test this model, we have carried out CA3-specific analyses of in vitro postmortem tissue using molecular markers of synaptic strength. We postulated an increase in CA3 perfusion downstream to CA1 and increase in markers of synaptic strength limited to CA3. We report an increase in GluN2B/GluN1 in CA3 (p=0.009) but fail to find any change in GluN2B/GluN1 in CA1 (p=0.34). Consistent with the increase of this protein in CA3 we also identify elevation of PSD-95, a change that is only apparent in CA3 (p=0.01). These changes were sustained in tissue drug-free at the time of death, confirming them as associated with disease, not medication. GAD-67 protein was unchanged in CA3 (p=0.64) and in CA1 (p=0.698). In an exploratory analysis of related synaptic proteins, we show a weak increase in GluN2A/GluN1 p=0.05) and a trend toward an increase in SAP-102 (p=0.07) all in CA3, and with the P-CREB/CREB significantly decreased in CA1 (p=0.05). We interpret these findings to confirm our hypothesis of an increase in synaptic strength in CA3 with increased neural activity in the Schaffer Collaterals onto CA1 neurons and suggest that this is mediated through increased number and sensitivity of the postsynaptic NMDA receptors in CA3. We propose that this increase in synaptic strength creates a risk state for psychosis which can be overwhelming in itself or can be activated by separate afferents (perhaps representing stress-related signaling) which act on high synaptic strength in CA3 to generate a ‘run away’ positive feed forward signaling within the recurrent collateral pathways in CA3. This could pervert normal associational activity in hippocampal CA3 (ProgBrainRes 169:225, 2008) and generate psychotic phenomena.
Lay Language Summary: Schizophrenia is a complex psychiatric condition whose pathophysiology has not yet been identified, even though considerable data are accumulating to provide clues regarding its mechanisms. Multiple brain regions are involved in schizophrenia, likely because there are multiple and multifaceted disease manifestations. We have been studying the role of the hippocampus in psychosis in schizophrenia. The hippocampus is the region of brain which is essential for the formation of new memories, during declarative memory processing. The anatomy of hippocampus is distinctive in having several defined subfields (dentate gurus, CA3, CA2, CA1, and subiculum) which have distinct and, in some regards, sequential functions in memory formation. Using high resolution human brain imaging approaches, we and others have identified an increase in neuronal activity in hippocampus, increases measured in both rCBF and rCBV. In this 2013 SFN poster, we show outcomes detailing an examination of postmortem hippocampal tissue donated by individuals with schizophrenia and comparison normals. We examined the hippocampal tissue to identify molecular and cellular markers consistent with hippocampal hyperactivity in the disease. We took hippocampal samples from 20 postmortem cases with schizophrenia (10 from cases treated with medication at the time of death and 10 from cases drug free at the time of death) and from 20 healthy cases. We micro-dissected the hippocampal subfields to distinguish the location of any changes within subfields of hippocampus. In CA3, we saw dramatic changes. These included a significant increase in GluN2B-containing NMDA receptors. This is the developmentally-predominant form of the NMDA glutamate receptor which passes more current per afferent signal, hence can magnify neuronal activity. It is known to be involved in and serve as a marker of increased neuronal activity. Consistent with this observation, we also show an increase in PSD95, which is the post-synaptic protein which holds the NMDA receptor tethered to the surface of the postsynaptic membrane. Also, we show an increase in the GluN2B/GluN2A receptor ratio in the drug-free schizophrenia sample, showing a predominance of the GluN2B form of the NMDA receptor. Interestingly, when we checked for these molecular markers of increased cellular activity in CA1, we found no such changes, suggesting that CA3 is the driver of hippocampal hyperactivity in schizophrenia. Based on this evidence of molecular changes supporting increased neuronal activity in CA3, we tested schizophrenia and control tissue using Golgi staining to quantify spine number and dendritic length in CA3, since increased spine number and dentrite enlongation are both anatomic markers of the consolidation of increased neuronal activity in tissue. Using Golgi stained tissue, we found a substantial and significant increase in spine number in the area of the afferent synapses from the mossy fiber pathway on the CA3 pyramidal cell apical dendrite; the size of the synapses (call Thorny Excresences, TE) were increased at a strong trend level. At the insertions of the recurrent collateral fibers in the proximal axonal region, there was no increase in spine number, however, the terminal dendrites within this area (stratum oriens) were longer, also a marker of increased neuronal activity. These molecular and cellular changes together suggest that within CA3 but not within CA1, pyramidal cell activity is increased in schizophrenia. We have previously articulated the hypothesis that an increase in CA3 pyramidal cell activity could be associated with an increase in the association of memories and, if pathological, could generate memories with a psychotic content. We propose that this might be a critical part of the molecular and cellular basis for the generation of psychosis in schizophrenia.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit