Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders

Abstract

Abnormalities in brain-derived neurotrophic factor (BDNF)/trkB signaling have been implicated in the etiology of schizophrenia and mood disorders. Patients with schizophrenia, bipolar disorder (BPD) and major depression (MDD) have reduced levels of neurotrophins in their brains when compared with normal unaffected individuals; however, only a few brain areas have been examined to date. Owing to the broad range of symptoms manifested in these disorders, we hypothesized that multiple associative areas of the neocortex may be implicated and that the degree of change in BDNF and trkB-TK+ mRNA expression and the cortical region or layers involved may vary according to Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis. We compared BDNF and trkB-TK+ mRNA levels across all layers of the prefrontal cortex (dorsolateral prefrontal cortex, DLPFC), orbital frontal cortex (OFC), anterior cingulate cortex (ACC), inferior temporal gyrus (ITG) and superior temporal gyrus (STG) in four groups: schizophrenia, BPD, MDD and unaffected controls (n=60). BDNF mRNA levels were significantly decreased in layers IV and V of DLPFC in schizophrenia patients, in layer VI of ACC in schizophrenia and MDD and in layer VI of ITG in schizophrenia, BPD and MDD. BDNF mRNA levels were also significantly decreased in layer V and/or VI of STG in schizophrenia, BPD and MDD. TrkB-TK+ mRNA levels were only significantly decreased in the cortical layer VI of OFC in BPD. The shared and distinct patterns of neurotrophin transcript reductions, with some specific to each group, may compromise the function and plasticity of distinct cortical areas to various degrees in the different groups and contribute to the range and overlap of symptoms manifested across the diagnoses.

Figure 1

Representative autoradiographic film images of BDNF (a–e) and trkB−TK+ (f–j) mRNA hybridization signal in the prefrontal cortex (a, f), cingulate cortex (b, g), orbital frontal cortex (c, h), superior temporal gyrus (d, i) and inferior temporal cortex (e, j).

Figure 2

Profiles showing the mean BDNF mRNA levels (μCi g⁻¹) for schizophrenia (pink), depression (light blue), bipolar disorder (yellow) and normal controls (dark blue), as a function of distance from the pial surface (a) DLPFC, (c) ACC, (e) OFC. Percentages on the x axis refer to proportion of total cortical width occupied by specific lamina. Post hoc testing revealed (b) schizophrenia group with significantly less BDNF mRNA than controls in layers IV and V of DLPFC and (d) schizophrenia and depressed with significantly less BDNF mRNA than controls in layer VI of ACC. *P<0.05, **P<0.01.

Figure 3

Profiles showing the mean BDNF mRNA levels (μCi g⁻¹) for the schizophrenia (pink), depression (light blue), bipolar disorder (yellow) and normal controls (dark blue), as a function of distance from the pial surface (a) STG, (c) ITG. Percentages on the x axis refer to proportion of total cortical width occupied by specific lamina. Post hoc testing revealed (b) schizophrenia group with significantly less BDNF mRNA than controls in layers V and all three diagnostic groups with significantly less BDNF mRNA than controls in layer VI of STG and (d) all three diagnostic groups with significantly less BDNF mRNA than controls in layer IV of ITG. *P<0.01.

Figure 4

Profiles showing mean trkB−TK+ mRNA levels (μCi g⁻¹) for the schizophrenia (pink), depression (light blue), bipolar disorder (yellow) and normal controls (dark blue), as a function of distance from the pial surface (a) DLPFC, (b) ACC, (c) OFC, (e) STG, (f) ITG. Percentages on the x axis refer to the proportion of total cortical width occupied by specific lamina. Post hoc testing revealed (d) bipolar disorder with significantly less trkB−TK+ mRNA than controls in layers VI. *P<0.005.

Figure 5

The mean BDNF and trkB−TK+ mRNA levels of individuals on antidepressants (a, b) or mood stabilizers (c) at the time of death compared with patients free of antidepressants or mood stabilizers at the time of death and to unaffected controls. (a) BDNF levels were significantly reduced in DLPFC layers II (P=0.006) and V (P=0.01) in patients not taking any antidepressants at the time of death as compared with the controls. (b) TrkB−TK+ levels were significantly reduced in OFC layers IV (P=0.008) and VI (P=0.001) in patients not taking any antidepressants at the time of death as compared with controls. (c) TrkB−TK+ mRNA levels were significantly reduced in OFC layer IV (P=0.01), in ACC layers III (P=0.02), Va (P=0.002) and Vb (P=0.01) and in ITG layers II (P=0.0006), III (P=0.004), IV (P=0.015) and V (P=0.01) in the patient group not taking any mood stabilizers at the time of death as compared with the controls groups.