Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia

Abstract

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.

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

“…Although population studies have yielded divergent data about the association of variants in the BDNF gene with increased risk and developmental features of schizophrenia, [72][73][74][75][76][77][78] human postmortem studies suggest that individuals with schizophrenia have reduced expression of TrkB and BDNF in the cerebral cortex, 12,[79][80][81][82] as well as decreased BDNF protein levels in the serum. 83 In addition, various animal models of schizophrenia consistently show a downregulation of BDNF transcript or protein.…”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…Likewise, potential contributions to weight gain of norepinephrine (Elman et al, 2002(Elman et al, , 2004 and prolactin (Melkersson, 2005;Mann et al, 2006) increases associated with SGA treatment are still unclear. The findings of SGA effects on the brain BDNF (Bai et al, 2003;Luo et al, 2004;Angelucci et al, 2005) and orexin in preclinical literature may be also of potential importance as both neurochemicals are involved in reward and appetitive functions; however, their precise role and how they are influenced by SGAs in humans (Dalal et al, 2003;Weickert et al, 2005) are intriguing topics for future research. In addition, further studies are needed to examine a potential involvement of the endogenous cannabinoid system that has been implicated in schizophrenia (Weiser and Noy, 2005), in obesity (Engeli et al, 2005), and in the mechanisms of action of SGAs, for example, clozapine (Sundram et al, 2005).…”

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

“…NGF, BDNF, and glucocorticoids regulate the expression of ChAT, enhance the connectivity of, and promote the survival of cholinergic neurons (Fagan et al, 1997;Grosse et al, 2005;Guijarro et al, 2006;Johnston et al, 1987;Mobley et al, 1986;Phillips et al, 2004;Sofroniew et al, 2001;Takahashi, 1998;Takahashi and Goh, 1998;Ward and Hagg, 2000). Reports have demonstrated altered regulation of NGF (Parikh et al, 2003), BDNF (Weickert et al, 2003(Weickert et al, , 2005, and the HPA axis (Corcoran et al, 2001(Corcoran et al, , 2003 in schizophrenics. Whether these changes alter corticostriatal cholinergic tone remains to be seen.…”