Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention

Abstract

Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia-from the premorbid through the prodromal stages to syndromal psychosis-and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.

Figure 1

(a) Coronal and sagittal MR images showing specific left hippocampal CA1 subregion with elevated CBV in high risk patients as compared to healthy volunteers. (b) Scatterplot showing the relationship between psychotic symptoms (delusional severity, hallucinations not shown) and left hippocampal CA1 CBV in high risk (black) and schizophrenia (red) patients. (c) Bar graph of CBV values in left hippocampal CA1 subregion ranging from posterior (top) to anterior (bottom) showing significantly increased activity of latter in patients who progressed to psychotic disorders and those who did not.

Figure 2

Relationship hippocampal CBV and atrophy. Hypermetabolism and atrophy of the hippocampus were strongly associated in anterior regions of the CA1 region but not in posterior or mid-regions.

Figure 3

Regional patterns of increased metabolic activity in hippocampus of patients with schizophrenia (a, c) and induced by acute ketamine in mice (BD). (a) (Left) Coronal image of human brain showing location of hippocampus and (Right) enlarged image of hippocampus with yellow highlight of regions showing trending (subiculum) or significantly higher CBV values in schizophrenia patients relative to controls. (b) (Left) Horizontal image of mouse brain showing location of hippocampus and (Right) enlarged image of hippocampus with yellow highlight of regions showing trending (subiculum) or significantly higher CBV values in schizophrenia patients relative to controls. (c, d). Stacked bar graphs showing relative hyperactivity (increased CBV) in patients with schizophrenia relative to controls (c) following systemic ketamine (30 mg/kg) in mice (d). The pattern induced by ketamine with greatest deviation in CA1, then SUB, and non-significant in other regions. (Adapted from data in Schobel et al.

Figure 4

Parallel increases in extracellular glutamate and CBV following ketamine and blockade by the mGluR 2/3 agonist and glutamate release inhibitor LY379268. (a) Extracellular glutamate measured with amperometry. (b) Overlay of time courses of ketamine-induced increases of glutamate (black) and CBV (red line). (c) Relative to saline pretreatment (red line), LY379268 pretreatment (purple line) blocks ketamine-induced increases in extracellular glutamate. (d) Similar blockade effect of LY379268 pretreatment in ketamine-induced increase in CBV.

Figure 5

(a) Rendering of hippocampus within the mouse brain (A.1) and zoom-in of hippocampus (A.2) showing area of greatest morphological change produced by repeated ketamine treatment. (b) Repeated ketamine exposure (16 mg/kg, 3 × per week, 4 weeks)(open circles) blocks the normal growth of the hippocampus across the transition to adulthood in mice, leading to a reduction in volume relative to saline controls (gray circles). (c) Mice receiving repeated treatments with saline only (gray bars and circles), ketamine with saline pre-treatment (red) or ketamine with pre-treatment with the mGlurR 2/3 agonist LY347268 (blue). LY347268 co(pre)-treatment blocks the increase in basal CBV (c1) and relative loss of hippocampal volume (c2) produced by repeated ketamine exposure. (d). Parvalbumin expressing neurons in dorsal hippocampus of the mouse. (e) Correlation between PV+ neuron density and CA1 CBV; loss of PV+ interneurons is associated with increased CBV. (f). Hippocampal volume loss correlates with increases in CBV.