Hippocampal hyperactivity has been proposed as a biomarker in schizophrenia. However, there is a debate whether the CA1 or the CA2/3 subfield is selectively affected. We studied 15 schizophrenia patients and 15 matched healthy control subjects with 3T steady state, gadolinium-enhanced, absolute cerebral blood volume (CBV) maps, perpendicular to the long axis of the hippocampus. The subfields of the hippocampal formation (subiculum, CA1, CA2/3, and hilus/dentate gyrus) were manually segmented to establish CBV values. Comparing anterior CA1 and CA2/3 CBV between patients and controls revealed a significant subfield-by-diagnosis interaction. This interaction was due to the combined effect of a trend of increased CA1 CBV (p = .06) and non-significantly decreased CA2/3 CBV (p = 0.14) in patients relative to healthy controls. These results support the emerging hypothesis of increased hippocampal activity as a biomarker of schizophrenia and highlight the importance of subfield-level investigations.

Previous studies in psychosis patients have shown hippocampal volume deficits across anterior and posterior regions or across subfields, but subfield specific changes in volume along the hippocampal long axis have not been examined. Here, we tested the hypothesis that volume changes exist across the hippocampus in chronic psychosis but only the anterior CA region is affected in early psychosis patients. We analyzed structural MRI data from 179 patients with a non-affective psychotic disorder (94 chronic psychosis; 85 early psychosis) and 167 heathy individuals demographically matched to the chronic and early psychosis samples respectively (82 matched to chronic patients; 85 matched to early patients). We measured hippocampal volumes using Freesurfer 6-derived automated segmentation of both anterior and posterior regions and the CA, dentate gyrus, and subiculum subfields. We found a hippocampal volume deficit in both anterior and posterior regions in chronic psychosis, but this deficit was limited to the anterior hippocampus in early psychosis patients. This volume change was more pronounced in the anterior CA subfield of early psychosis patients than in the dentate gyrus or subiculum. Our findings support existing models of psychosis implicating initial CA dysfunction with later progression to other hippocampal regions and suggest that the anterior hippocampus may be an important target for early interventions.

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Neuroimaging studies have provided compelling evidence for abnormal hippocampal activity in schizophrenia. Most studies made inferences about baseline hippocampal activity using a single hemodynamic parameter (e.g., blood volume or blood flow). Here we studied several hemodynamic measures in the same cohort to test the hypothesis of increased hippocampal activity in schizophrenia. We used dynamic susceptibility contrast- (DSC-) magnetic resonance imaging to assess blood volume, blood flow, and mean transit time in the hippocampus of 15 patients with chronic schizophrenia and 15 healthy controls. Left and right hippocampal measurements were combined for absolute measures of cerebral blood volume (CBV), blood flow (CBF), and mean transit time (MTT). We found significantly increased hippocampal CBV, but normal CBF and MTT, in schizophrenia. The uncoupling of CBV and CBF could be due to several factors, including antipsychotic medication, loss of cerebral perfusion pressure, or angiogenesis. Further studies need to incorporate several complementary imaging modalities to better characterize hippocampal dysfunction in schizophrenia.

Recent evidence suggests that the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is involved in the pathology of Huntington’s Disease (HD). While animals lacking PGC-1α express lower levels of genes involved in antioxidant defense and oxidative phosphorylation in the brain, little is known about other targets for PGC-1α in neuronal cells and whether there are ways to pharmacologically target PGC-1α in neurons. Here, PGC-1α overexpression in SH-SY5Y neuroblastoma cells upregulated expression of genes involved in mitochondrial function, glucose transport, fatty acid metabolism, and synaptic function. Overexpression also decreased vulnerability to hydrogen peroxide-induced cell death and caspase 3 activation. Treatment of cells with the histone deacetylase inhibitors (HDACi’s) trichostatin A and valproic acid upregulated PGC-1α and glucose transporter 4 (GLUT4). These results suggest that PGC-1α regulates multiple pathways in neurons and that HDACi’s may be good candidates to target PGC-1α and GLUT4 in HD and other neurological disorders.