Season of birth in schizophrenia: a maternal-fetal chronobiological hypothesis.

Being born in the winter and spring significantly increases one's risk for developing schizophrenia. This birth seasonality may account for as many as 10% of all cases of schizophrenia. Maternal third trimester infections or vitamin D deficiencies are hypothesized to be the most likely cause and can account for many of the important features of schizophrenia, although each hypothesis has limitations. Alternatively, around the winter solstice, reduced maternal sunlight exposure during the second trimester of pregnancy may result in a reduced amplitude maternal circadian pacemaker, reduced maternal nocturnal plasma melatonin concentrations, elevated maternal nocturnal core body and incubator temperatures, and elevated fetal core body and brain temperatures. Indeed, studies in humans have shown that the core body temperatures of human fetuses near birth may vary by >2.5°C. Reduced melatonin concentrations and elevated temperatures have been shown to have detrimental effects on immature hippocampal neurons in animals. In addition, plasma melatonin concentrations and core body temperatures are critical determinants of the dopaminergic programming of the striatal component of the human central thermostat, which appears to be functioning by the second trimester of gestation and responsive to whatever chronobiological signals its mother correctly or incorrectly transduces from the prevailing meteorological conditions. Both hippocampal and striatal thermostat dysfunction may result in reduced striatal extracellular dopamine concentrations and a tendency towards increased phasic dopamine release-the characteristic biochemical lesion in schizophrenia. Thus, the maternal-fetal chronobiological dysfunction hypothesis could account for the birth seasonality in schizophrenia and warrants further investigation.