Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK þ )-containing form of trkB and measured pan trkC mRNA in schizophrenics (N ¼ 14) and controls (N ¼ 15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkB TK þ mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkB TK þ mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkB TK þ mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkB TK þ was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia. Molecular Psychiatry (2005) 10, 637-650.

Signalling through tyrosine kinase receptor B (trkB) influences neuronal survival, differentiation and synaptogenesis. trkB exists in a full-length form (trkB(TK+)), which contains a catalytic tyrosine kinase (TK) domain, and a truncated form (trkB(TK-)), which lacks this domain. In the rodent brain, expression of trkB(TK+) decreases and trkBTK- increases during postnatal life. We hypothesized that both forms of trkB receptor mRNA would be present in the human neocortex and that the developmental profile of trkB gene expression in human may be distinct from that in rodent. We detected both trkB(TK+) and trkB(TK-) mRNA in RNA extracted from multiple human brain regions by Northern blot. Using in situ hybridization, we found trkB(TK+) mRNA in all cortical layers, with highest expression in layer IV and intermediate-to-high expression in layers III and V of the human dorsolateral prefrontal cortex. trkB(TK+) mRNA was present in neurons with both pyramidal and nonpyramidal shapes in the dorsolateral prefrontal cortex. trkB(TK+) mRNA levels were significantly increased in layer III in young adults as compared with infants and the elderly. In the elderly, trkB(TK+) mRNA levels were reduced markedly in all cortical layers. Unlike the mRNA encoding the full-length form of trkB, trkB(TK-) mRNA was distributed homogeneously across the grey matter, and trkB(TK-) mRNA levels increased only slightly during postnatal life. The results suggest that neurons in the human dorsolateral prefrontal cortex are responsive to neurotrophins throughout postnatal life and that this responsiveness may be modulated during the human lifespan.

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