Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia.

Abstract

Dysfunction of inhibitory neurons in the prefrontal cortex (PFC), represented by decreased expression of GABA-related genes such as the 67 kDa isoform of glutamate decarboxylase (GAD67) and parvalbumin (PV), appears to contribute to cognitive deficits in subjects with schizophrenia. We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia. In 15 pairs of subjects with schizophrenia and matched control subjects, both BDNF and TrkB mRNA levels, as assessed by in situ hybridization, were significantly decreased in the PFC of the subjects with schizophrenia, whereas the levels of mRNA encoding the receptor tyrosine kinase for neurotrophin-3, TrkC, were unchanged. In this cohort, within-pair changes in TrkB mRNA levels were significantly correlated with those in both GAD67 and PV mRNA levels. Decreased BDNF, TrkB, and GAD67 mRNA levels were replicated in a second cohort of 12 subject pairs. In the combined cohorts, the correlation between within-pair changes in TrkB and GAD67 mRNA levels was significantly stronger than the correlation between the changes in BDNF and GAD67 mRNA levels. Neither BDNF nor TrkB mRNA levels were changed in the PFC of monkeys after a long-term exposure to haloperidol. Genetically introduced decreases in TrkB expression, but not in BDNF expression, also resulted in decreased GAD67 and PV mRNA levels in the PFC of adult mice; in addition, the cellular pattern of altered GAD67 mRNA expression paralleled that present in schizophrenia. Decreased TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia.

• Authors: Takanori Hashimoto, Sarah E Bergen, Quyen L Nguyen, Baoji Xu, Lisa M Monteggia, Joseph N Pierri, Zhuoxin Sun, Allan R Sampson, David A Lewis
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 25 Issue 2 Pg. 372-83 (Jan 12 2005) ISSN: 1529-2401 [Electronic] United States
• PMID: 15647480 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Dyskinesia Agents
• Antipsychotic Agents
• Brain-Derived Neurotrophic Factor
• RNA, Messenger
• Benztropine
• gamma-Aminobutyric Acid
• Receptor, trkB
• Haloperidol

Topics

• Adult
• Aged
• Animals
• Anti-Dyskinesia Agents (pharmacology)
• Antipsychotic Agents (pharmacology)
• Benztropine (analogs & derivatives, pharmacology)
• Brain-Derived Neurotrophic Factor (genetics, physiology)
• Case-Control Studies
• Female
• Gene Expression Regulation (drug effects)
• Haloperidol (pharmacology)
• Humans
• Macaca fascicularis
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Middle Aged
• Neural Inhibition (physiology)
• Prefrontal Cortex (physiopathology)
• RNA, Messenger (metabolism)
• Receptor, trkB (genetics, physiology)
• Schizophrenia (drug therapy, physiopathology)
• Signal Transduction (physiology)
• gamma-Aminobutyric Acid (genetics)