Deficits in Transcriptional Regulators of Cortical Parvalbumin Neurons in Schizophrenia

• Published in: American Journal of Psychiatry Vol. 169; no. 10; pp. 1082 - 1091
• Main Authors: Volk, David W, Matsubara, Takurou, Li, Siyu, Sengupta, Elizabeth J, Georgiev, Danko, Minabe, Yoshio, Sampson, Allan, Hashimoto, Takanori, Lewis, David A
• Format: Journal Article
• Language: English
• Published: Arlington, VA American Psychiatric Association 01.10.2012
• Subjects: Adult and adolescent clinical studies; Animals; Antipsychotic Agents - pharmacology; Biological and medical sciences; Calbindin 2; Genotype & phenotype; Humans; LIM-Homeodomain Proteins - deficiency; LIM-Homeodomain Proteins - genetics; Macaca fascicularis; Male; Medical sciences; Middle Aged; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Neurons; Neurons - metabolism; Parvalbumins - genetics; Parvalbumins - metabolism; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; RNA, Messenger - antagonists & inhibitors; S100 Calcium Binding Protein G - genetics; S100 Calcium Binding Protein G - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Schizophrenia - pathology; Somatostatin - genetics; Somatostatin - metabolism; SOXD Transcription Factors - genetics; SOXD Transcription Factors - metabolism; Transcription Factors - deficiency; Transcription Factors - genetics; Psychosis; Binding protein; Neuron; Calcium; Schizophrenia; Parvalbumin; Inorganic element
• ISSN: 0002-953X; 1535-7228; 1535-7228
• DOI: 10.1176/appi.ajp.2012.12030305

ObjectiveIn 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 neurons, but not calretinin neurons, and continue to be strongly expressed in this cell type-specific manner in the prefrontal cortex of adult humans. The authors 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.MethodThe authors used quantitative PCR and in situ hybridization with film and grain counting analyses to quantify mRNA levels in postmortem samples of prefrontal cortex area 9 of 42 schizophrenia subjects and 42 comparison subjects who had no psychiatric diagnoses in life, as well as antipsychotic-exposed monkeys.ResultsIn schizophrenia subjects, the authors observed lower mRNA levels for Lhx6, parvalbumin, somatostatin, and glutamate decarboxylase (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. Grain counting analyses revealed that some neurons that normally express Lhx6 were not detectable in schizophrenia subjects. Finally, lower Lhx6 mRNA levels were not attributable to psychotropic medications or illness chronicity.ConclusionsThese data suggest that in a subset of individuals with schizophrenia, Lhx6 deficits may contribute to a failure of some cortical parvalbumin and somatostatin neurons to successfully migrate or develop a detectable GABA-ergic phenotype.