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.