PV mRNA expression in the prefrontal cortex of monkeys was unaffected by long-term exposure to haloperidol.

Macalester College

- Abnormal prefrontal cortex circuitry and GABA neurotransmission in schizophrenia patients
- Expression of parvalbumin and calretinin mRNAs in area 9 of schizophrenic and control subjects
- Relationship to decreased GAD₆₇ mRNA expression in the prefrontal cortex of subjects with schizophrenia
- Parvalbumin mRNA expression in the prefrontal cortex of haloperidol-treated monkeys

Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia

Hashimoto, T., Volk, D. W., Eggan, S. M., Mirnics, K., Pierri, J. N., Sun, Z., Sampson, A. R., & Lewis, D. A. (2003). Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. The Journal of Neuroscience, 23(15), 6315–6326. https://doi.org/10.1523/jneurosci.23-15-06315.2003

Abnormalities in the circuitry of the prefrontal cortex can contribute to impairments in working memory, though in only a specific subsection of GABA neurons. Local circuit neurons regulating these types of functions in the prefrontal cortex show altered GABA neurotransmission. There was also reduced mRNA expression (below the level of detection) of glutamate decarboxylase (GAD₆₇), which is an enzyme responsible for making GABA in the prefrontal cortex, and GABA membrane transporter-1 (GAT-1) - which is seen in 25-35% of GABA neurons in the prefrontal corteces of those with schizophrenia.


Abnormal Prefrontal Cortex Circuitry & GABA Neurotransmission in Schizophrenia Patients

- Parvalbumin (PV) mRNA positive neurons were most highly distributed in prefrontal cortical layers II-IV. In schizophrenia patients, a 29% decrease in expression in layer III and a 35% decrease in layer IV was seen
- Calretinin (CR) mRNA positive neurons were most highly distributed in prefrontal cortical layers I and II. There was no significant difference in CR mRNA expression in these layers in patients with schizophrenia
- PV mRNA signals in area 9 of the prefrontal cortex are decreased in patients with schizophrenia but CR mRNA signals aren’t affected
- Average optical density of PV mRNA was decreased by 30% in patients with schizophrenia
- Grain density per PV mRNA-positive neuron showed a 22% decrease in patients with schizophrenia
- Since there’s a collective decrease in PV mRNA expression levels in patients with schizophrenia, the balanced signal intensity ratio for CR to PV mRNA expression was seen to be significantly higher in patients with schizophrenia
- PV mRNA reduction can’t be due to general deterioration of mRNA integrity in those with schizophrenia since CR mRNA (among other transcripts) didn’t differ between schizophrenia and control subjects
- Reduction in PV mRNA levels could reflect changes in transcriptional regulation secondary to genetic predisposition to schizophrenia


Expression of parvalbumin and calretinin mRNAs in area 9 of schizophrenic and control subjects

Overall, there was a significant correlation between reduced neuronal PV mRNA expression and a decreased density of GAD₆₇ mRNA-positive neurons in those with schizophrenia. There was a strong correlation when comparing the within-pair differences in GAD₆₇ mRNA-positive neuron density and the in grain density per PV mRNA-positive neuron. There was no correlation in the differences of GAD₆₇ mRNA-positive neuron density and in PV mRNA-positive neuron density. There was also no significant correlation in the differences of GAD₆₇ mRNA-positive neurons and CR mRNA-positive neuron density or grain density per CR mRNA-positive neuron. GAD₆₇ mRNA signals were undetectable in many (about 45%) PV mRNA-positive grain clusters - the amount of these neurons with undetectable signals was 4.5 times greater in those with schizophrenia. These results suggest that GAD₆₇ mRNA expression is deficit in schizophrenia patients only in a selective subclass of PV-containing GABA neurons in the prefrontal cortex


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