News

Study by Volk et al. Reveals Transcriptional Regulator
Deficits in Individuals with Schizophrenia

Deficits in Transcriptional Regulators of Cortical Parvalbumin Neurons in Schizophrenia
Volk DW, Matsubara T, Li S, Sengupta EJ, Georgiev D, Minabe Y, Sampson A, Hashimoto T, Lewis DA

An investigation by Dr. David Volk, Assistant Professor of Psychiatry, and colleagues suggests that a deficit in a transcription factor, Lhx6, may negatively influence the migration or functioning of some cortical parvalbumin and somatostatin neurons in schizophrenia subjects.

Alterations in the inhibitory circuitry of the prefrontal cortex in schizophrenia appear to be most prominent in GABA neurons that contain parvalbumin or somatostatin but not calretinin. The transcription factors Lhx6 and Sox6 play critical roles in the development of parvalbumin and somatostatin, but not calretinin, neurons and continue to be strongly expressed in this cell type-specific manner in the prefrontal cortex of adult humans. Therefore, Dr. Volk and colleagues investigated Lhx6 and/or Sox6 mRNA levels to determine if they are deficient in individuals with schizophrenia and thus might contribute to cell type-specific disturbances in cortical parvalbumin and somatostatin neurons.

Using quantitative PCR and in situ hybridization, they quantified mRNA levels in the prefrontal cortex of 42 schizophrenia and 42 healthy comparison subjects and in antipsychotic-exposed monkeys.  Results showed lower mRNA levels for Lhx6, parvalbumin, somatostatin, and GAD67 (the principal synthesizing enzyme for the inhibitory neurotransmitter, GABA), but not Sox6 or calretinin, in schizophrenia subjects. A subset of schizophrenia subjects also consistently showed the most severe deficits in the affected transcripts. The lower Lhx6 mRNA levels in schizophrenia could not be attributed to antipsychotic medications.

Taken together, these findings suggest that in a subset of schizophrenia subjects, Lhx6 deficits may contribute to a failure of some cortical parvalbumin and somatostatin neurons to successfully migrate or become fully functioning inhibitory neurons.

Contributors:

David Volk, MD, PhD, Elizabeth Sengupta, MAT, and David Lewis, MD (Department of Psychiatry, University of Pittsburgh)
Siyu Li, MA and Alan Sampson, PhD (Department of Statistics, University of Pittsburgh)
Takurou Matsubara, MD(Kanazawa University, Japan)
Danko Georgiev, MD, PhD and Takanori Hashimoto, MD, PhD (Department of Psychiatry, Kanazawa University, Japan)
Yoshio Minabe, MD, PhD (Department of Psychiatry and Neurology, Hamamatsu University School of Medicine)

The results of this study were published in the October 2012 issue of the American Journal of Psychiatry. Click here for a link to the abstract.