Decreased neurotrophic response to birth hypoxia in the etiology of schizophrenia

Abstract

Background: Obstetric complications, particularly fetal hypoxia, are associated with increased risk for schizophrenia later in life. Such factors are also related to increased severity of certain neuropathological features of schizophrenia, including hippocampal and cortical gray matter reduction, among individuals with a genetic susceptibility to the disorder. However, the molecular mechanisms underlying these associations are unknown. Here, we sought to determine whether neurotrophic factors, which are stimulated as part of a neuroprotective response to fetal distress, are differentially expressed in cord blood samples at the time of birth following fetal hypoxia, maternal hypertension/small for gestational age status, and/or prematurity among individuals who developed schizophrenia as adults, as compared with control subjects.

Methods: One hundred eleven cases with psychotic disorders (70 with schizophrenia) and 333 control subjects matched for gender, race, and date of birth were drawn from the Philadelphia cohort of the National Collaborative Perinatal Project in a nested case-control study. Brain-derived neurotrophic factor (BDNF) was assayed from cord and maternal blood samples taken at delivery and stored at -20 degrees C for 45 to 50 years.

Results: Among control subjects, birth hypoxia was associated with a significant (10%) increase in BDNF in cord samples, while among cases, hypoxia was associated with a significant (20%) decrease in BDNF. This differential response to fetal hypoxia was specific to schizophrenia and was not explained by other obstetric complications or by the BDNF valine (val) to methionine (met) polymorphism at codon 66 (val66met).

Conclusions: These findings provide serologically based prospective evidence of disrupted neurotrophic signaling in response to birth hypoxia in the molecular pathogenesis of schizophrenia.

Figure 1

Least-square mean (± SEM) BDNF levels in cord blood samples by fetal hypoxia in cases versus controls (as derived from the full mixed model analysis of variance shown in Table 2). While controls showed an increase in BDNF as a function of exposure to hypoxia, cases exposed to hypoxia showed a significant decrease in BDNF.