|In schizophrenia, alterations within the prefrontal cortical GABA system appear to be most prominent in neurons that contain parvalbumin or somatostatin but not calretinin. The transcription factors Lhx6 and Sox6 play critical roles in the specification, migration, and maturation 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, we investigated whether Lhx6 and/or Sox6 mRNA levels are deficient in schizophrenia, which may contribute to cell type¬specific disturbances in cortical parvalbumin and somatostatin neurons. We used quantitative PCR and in situ hybridization with film and grain counting analyses to quantify mRNA levels in prefrontal cortex area 9 of 42 schizophrenia and 42 healthy comparison subjects and in antipsychotic¬exposed monkeys. In schizophrenia subjects, we found lower mRNA levels for Lhx6, parvalbumin, somatostatin, and GAD67 (the principal enzyme in GABA synthesis), but not Sox6 or calretinin. Cluster analysis revealed that a subset of schizophrenia subjects consistently showed the most severe deficits in the affected transcripts. This subset of schizophrenia subjects had lower average mRNA levels for Lhx6, GAD67, parvalbumin, and somatostatin, but not calretinin or Sox6, relative to all other schizophrenia subjects and to healthy comparison subjects (see figure). Grain counting analyses revealed that some neurons that normally express Lhx6 were not detectable in schizophrenia. Finally, lower Lhx6 mRNA levels were not attributable to psychotropic medications or illness chronicity. These data 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 develop a detectable GABAergic phenotype.
|Volk DW, Matsubara T, Li S, Sengupta EJ, Georgiev D, Minabe Y, Sampson A, Hashimoto T, Lewis DA: Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia. Am J Psychiatry 169:1082-1091, 2012