Relating the Effects of Prenatal Stress in Rodents to the Pathogenesis of Schizophrenia

Abstract

s t t a s c t T he study by Escobar et al. (1) in this issue shows that exposure of the pregnant rat dam at day 19 of gestation to a bacterial endotoxin, a manipulation used to model maternal immune ctivation (MIA), leads to abnormal postnatal development of synptic long-term depression (LTD) in the CA3-CA1 hippocampal ciruit in the offspring. The form of LTD they examined is induced by ow-frequency stimulation of the glutamatergic efferents from CA3, hich synapse extensively onto the dendrites of the CA1 projection eurons. The study shows that in neonatal brains from control and MIAxposed offspring, LTD in the CA3-CA1 circuit induced by a train of ow-frequency stimuli is prominent and depends on N-methyl-Dspartate (NMDA) receptors and downstream messengers. This LTD ormally decreases across postnatal development; however, MIAxposed offspring show a more rapid developmental reduction, osing this form of plasticity altogether by the late juvenile period. he authors also found a parallel developmental loss of NMDA relative to 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid AMPA]) currents in CA1 neurons of MIA offspring but do not adress whether this is causally related to the developmental loss of TD. They added a more preliminary finding, that MIA offspring also how abnormal ontogeny, particularly evident in the late juvenile eriod, of a different form of synaptic plasticity regulated in part by etabotropic glutamate receptors. Taken together, the findings upport the hypothesis that MIA leads to changes in mechanisms egulating synaptic plasticity in the CA3-CA1 circuit that may, in urn, be hypothesized to have a profound and persistent impact on he ability of CA1 neurons to integrate input signals from other ippocampal subregions, the subiculum, the entorhinal and paraippocampal cortices, and the limbic basal forebrain (1,2). Many believe that the study by Escobar et al. (1) and similar tudies have important implications for the pathogenesis and exression of schizophrenia. Unpacking the assumptions underlying his belief, however, can reveal critical gaps in knowledge that emain to be filled to build a theory linking prenatal maternal stress xposure to neural circuit dysfunction in schizophrenia. Below we llustrate some of the domains of knowledge and the gaps among hem. We start with the evidence linking prenatal stressors to the risk or schizophrenia in the offspring. Epidemiologic studies have hown that adverse maternal exposures during gestation, includng various nutritional deficiencies, infections, and toxins, are assoiated with increased risk for neurodevelopmental disorders in chilren, and some specifically to disorders, such as schizophrenia, enerally diagnosed after puberty ([3]; see also reference 2 in Escoar et al). Although it is not yet clear which of these findings will