Schizophrenia focus narrowed to dentate gyrus

By Eleanor McDermid, Senior medwireNews Reporter

The dentate gyrus is a likely site of pathology underlying schizophrenia, shows a study published in Molecular Psychiatry.

The findings, which incorporate brain imaging, postmortem findings and an animal study, indicate that reduced glutamate concentrations in the dentate gyrus are sufficient to account for the low levels seen in the hippocampus in patients with schizophrenia.

The researchers, led by Ana Stan (UT Southwestern Medical Center, Dallas, Texas, USA), say that their results imply a “unique pathological characteristic” of dentate gyrus function in patients with schizophrenia.

The team found that glutamate levels in the hippocampus, measured using proton magnetic resonance spectroscopy (MRS), were significantly lower in 18 patients with schizophrenia than 16 matched mentally healthy controls.

These findings were supported by the postmortem study, of hippocampal tissue from 11 schizophrenia patients and 11 matched controls. Relative to the controls, patients had significantly reduced levels of GluN1 – a subunit of the N-methyl-D-aspartate receptor, which binds glutamate. More precisely, there were reduced levels in the dentate gyrus subfield, but not the CA1 and CA3/2 subfields.

Stan and team then studied genetically modified mice that lacked GluN1 specifically in the dentate gyrus. Despite the specificity of this modification, on proton MRS the mice exhibited a significant reduction in glutamate concentration for the entire hippocampus, suggesting that reduced dentate gyrus levels are sufficient to explain the hippocampal changes seen in patients.

By contrast, there were no significant changes in measures of inhibitory neurotransmission: gamma-aminobutyric acid (GABA) levels in patients and mice, and glutamic acid decarboxylase (the main enzyme in GABA synthesis) in postmortem samples.

Although the lack of change was consistent between these measures, the researchers note that the data did not exclude the possibility of detecting significantly reduced GABA levels in a larger sample, for both the patients and the mice. Indeed, other studies have shown “very specific, cell population level, abnormalities” in inhibitory neurotransmission, they say.

If this were the case, they suggest that this reduction could be “a compensatory mechanism meant to restore the hippocampal excitation/inhibition balance.”

Furthermore, Stan and co-workers stress that the neurotransmission markers they chose were “not exhaustive.” They conclude: “Markers of [glutamate] signaling are multiple and complex, so thorough testing of [glutamate] signaling in hippocampus as a whole will take further study.”

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