The Origins of Schizophrenia

Concern for the health of the fetus following maternal stress has existed at least since the age of Hippocrates (Huizink et al., 2004). Highly traumatic events during pregnancy, such as death of a close relative or a severe threat to one’s safety, are associated with prematurity and low birth weight in the offspring (Mulder et al., 2002; Gennaro & Hennessy, 2003; Hobel & Culhane, 2003). There is also a report of neural malformations in the offspring of mothers who experienced the death of an older child during the first trimester (Hansen, Lou, & Olsen, 2000). Regarding schizophrenia, epidemiologic studies of an ecologic nature have associated increased risk to the offspring with maternal exposure to any of a variety of stressful events (chapter 4, this book). These studies were not able to examine the risk in individual cases, however. Thus, it is important that a recent study followed the life course of subjects from gestation to adulthood and showed an increased risk for schizophrenia and psychosis in the offspring of mothers exposed to the death of a first-degree relative during the first trimester (Khashan et al., 2008). Other prospective studies reported an association of schizophrenia with unwanted pregnancy or death of the father during gestation (Huttunen & Niskanen, 1978; Myhrman et al., 1996). Maternal stress also increases the risk to the offspring of attentional deficit, hyperactivity, anxiety, and language delay (Talge, Neal, & Glover, 2007; Weinstock, 2008; Goel & Bale, 2009; Schlotz & Phillips, 2009).

It is perhaps surprising that epidemiologic studies have revealed these significant associations, as stress is a highly individual, idiosyncratic experience. What is perceived as very traumatic to one person may be a momentary setback to another. This variation is likely due to genetic background, as well as to prior life experience and available social support systems. Moreover, biomarkers of stress have not been used in these human studies, although cortisol assays have been employed in related work. It is therefore important that experiments with rodent and nonhuman primate models have provided strong support for the overall conclusions of the human studies (reviewed by Koenig, Kirkpatrick, & Lee, 2002; Kofman, 2002; Huizink et al., 2004; Bale, 2005; Viltart & Vanbesien-Mailliot, 2007; Beydoun & Saftlas, 2008; Weinstock, 2008). These animal experiments have defined various factors that can influence the outcome of maternal stress and have described structural changes in the brains of the offspring. Some of the effects of maternal stress even continue beyond the adult offspring, extending to the second generation of progeny (Drake, Walker, & Seckl, 2005). The animal studies have also revealed insights into the mechanisms mediating the effects of maternal stress on the fetus and the resulting behavioral abnormalities in the adult offspring. Most of those experiments have focused on the role of the hypothalamic-pituitary-adrenal (HPA) axis and particularly on glucocorticoids (GC) (figure 13.1).

For brevity, this review cites previous reviews instead of primary articles wherever possible.

Although in this field the most common terminology used is prenatal stress, the present review uses the term maternal stress because the former phrase may suggest that the stress is applied directly to the fetus, whereas the latter phrase more precisely describes the manipulation. That is, stress is applied to the mother, whose response may then affect the fetus. The types of animals used in these experiments include rats, mice, voles, guinea pigs, sheep, pigs, and nonhuman primates (rhesus monkeys, common marmosets, and African vervets). Rats have been the overwhelmingly popular choice of subject, with very few studies on mice, which is surprising given their utility for genetic manipulation. One form of experimental manipulation is termed psychosocial or naturalistic stress: crowding in the home cage, confrontation with an intruder in the home cage, or exposure to a novel environment or a predator. A novel form of psychological stress involves showing a pregnant rat another rat being subjected to electric shocks on the other side of a transparent wall (Abe et al., 2007). A second category of stress is termed physical stress: daily handling, loud noise or acoustic startle stimuli, strobe light stimulation, restraint in a ventilated plastic tube in the presence or absence of bright lights, swimming in water for 15 minutes a day, elevated or cold temperature (4° for six hrs a day), placing the cage or animal on a rotating platform, subcutaneous injection of saline, or electric foot shocks. Variable stress paradigms have also been used, such as restraint, swimming, cold exposure, fasting overnight, overcrowding social stress, lights on overnight, and cold exposure, applied in pseudorandom fashion during three periods of the day for a week (Koenig et al., 2005). Since maternal stress activates the HPA axis, a more defined form of the model involves administration of GC to the mother, mimicking the natural rise in this hormone that follows behavioral stress. This model can utilize the GC that is physiologically relevant for the species of interest, or the synthetic GC, dexamethasone (Dex), which crosses the placenta freely.

The timing of the induction of maternal stress is an important factor in the outcome for the offspring. For instance, hippocampal-dependent learning and memory in rats are influenced by the timing of the stress. Such work has also shown a dependence on the stage of the estrous cycle in female offspring and the sex of the offspring (Goel & Bale, 2009). In guinea pigs, stress applied during the period of rapid brain growth or during very late gestation produces very different effects on HPA axis activity (Kapoor & Matthews, 2008). Stress during the former period causes changes in the hippocampus, hypothalamus, anterior pituitary, and adrenal cortex. The most common treatment window in rat studies is the last week of pregnancy. However, altered behavior has also been seen in the adult offspring of dams exposed to stress as long as two weeks before conception (Shachar-Dadon, 2009). Striking results have also been obtained using variable stress during very early pregnancy in mice (E1–7) (Mueller & Bale, 2008). This is surprising given that the brain has yet not formed at this time, but it is consistent with the epidemiologic study of individual human subjects, which has implicated first-trimester exposure to maternal stress as a risk factor for schizophrenia (Khashan et al., 2008; see chapter 4, this book). This observation underscores the importance of the placenta in the response to maternal stress, and this tissue undergoes key developmental changes during this period. Another point of interest regarding the placenta is that it contains many immune cells (Koga et al., 2009), which is an important but unexplored aspect of how maternal stress evokes immune changes in the offspring. The roles of the placenta and the immune system are considered later in this review.

The adult offspring of animals stressed during pregnancy display a variety of abnormal behaviors, including elevated levels of anxiety and responses to novelty, more learned helplessness in the forced swim test, greater vulnerability to psychostimulants, a phase advance in the circadian rhythm of locomotor activity, and an increase in paradoxical sleep (Talge, Neal, & Glover, 2007; Darnaudery & Maccari, 2008; Thomas et al., 2009). Depending on their gender, age, gestational stage, severity of the stress, and the task, adult offspring can display increased conditioned and context fear conditioning, deficits in play and other social behavior, defensive freezing, learning and memory ability, and long-term potentiation (LTP) (Griffin et al., 2003; Fumagalli et al., 2007; Mueller & Bale, 2007; Darnaudery & Maccari, 2008; Kapoor et al., 2009). Behavioral alterations have also been observed in young pups born to stressed dams (Harmon et al., 2009). Many of these changes, such as increased immobility in the forced swim test, are consistent with behaviors found in human major depressive disorder. Moreover, chronic treatment with antidepressant drugs in the adult offspring can be effective in correcting some of these behaviors in the rat maternal stress model (Morely-Fletcher et al., 2004).

As in schizophrenia, the adult offspring of pregnant rats exposed to variable stress exhibit a deficit in sensorimotor gating, as measured by the N40 auditory evoked response (Koenig et al., 2005). In contrast, in two other behavioral tests with strong relevance for schizophrenia, prepulse inhibition (PPI) and latent inhibition (LI), the results are mixed. Deficits in PPI are found in schizophrenic subjects, and in animal models with relevance to this disorder such as maternal infection, immune activation (Patterson, 2009), and neonatal ventral hippocampus lesion (Lipska & Weinberger, 2000). Moreover, both dopaminergic and glutamatergic psychomimetic drugs disrupt PPI in humans and animals. Using a variable stress paradigm with pregnant rats, Koenig et al. (2005) found a significant PPI deficit in adult male, but not female, offspring. On the other hand, Lehmann, Stohr, and Feldon (2000), using maternal restraint stress, reported increased PPI in male and female offspring, whereas Hauser, Feldon, and Pryce (2006), using the maternal Dex model, reported inconclusive PPI results. Although the different rat strains and maternal stress paradigms used in these studies undermine strict comparisons of the results, the available data do not lend strong support for a PPI deficit in the maternal stress paradigm.

Latent inhibition is another sensorimotor gating assay, but involves a neuroanatomic pathway different from that of PPI. Antipsychotic drugs can potentiate LI in schizophrenic subjects and in animals, and LI is abolished by amphetamine, which exacerbates symptoms in schizophrenia. Moreover, LI is absent in some schizophrenic subjects (Weiner, 2003). Shalev and Weiner (2001) reported that maternal restraint stress has no effect on LI in the adult offspring, whereas maternal foot shock or corticosterone administration leads to a LI deficit in the male, but not female, offspring. On the other hand, Hauser, Feldon, and Pryce (2006), using maternal Dex administration, found no evidence for LI disruption, and Bethus et al. (2005), using maternal restraint, reported an increase in LI in the offspring. If the precise method of maternal stress is critical for producing an LI deficit (Shalev & Weiner, 2001), then these studies cannot be directly compared. Moreover, different assays for LI were used. As with PPI, the available data do not provide significant support for a schizophrenia-like sensorimotor gating deficit in the maternal stress paradigm.

There is an interaction between the severity of maternal stress administered and the gender of the offspring in the outcome of behavioral changes. That is, with mild maternal stress in rats, a selective induction of anxiety in females and learning deficits in males is seen (Zagron & Weinstock, 2006). Male offspring are more likely to display deficits in learning, LTP, hippocampal neurogenesis, and dendritic spine density in the prefrontal cortex and areas CA1 and CA3 of the hippocampus (Weinstock, 2007; Martinez-Tellez et al., 2009). With stronger maternal stress, anxiogenic behavior is observed in both sexes. In fact, female offspring appear to be more prone to exhibit changes in the HPA axis and display depressive-like behavior. Differences have also been reported between the stress responses of the male and female fetal rat hypothalamus and pituitary, including hormone and neurotransmitter release (Ohkawa et al., 1991). Maternal stress in humans also causes abnormal regulation of HPA axis responses in adult female offspring. Cortisol responses are lower in maternal stress-exposed offspring than in controls following a social stress test or adrenocorticotropin hormone (ACTH) injection (Entringer et al., 2009).

Studies of maternal stress in monkeys have revealed several complexities in the analysis of offspring behavior that have not been fully appreciated in rodent work (Coe & Lubach, 2005). For instance, these “emotionally reactive” offspring tend to be lower in the group’s social hierarchy as adolescents. This subordinate rank may magnify their emotionality, or may induce novel behaviors on its own. Because social rank also affects the stress response in rodents (e.g., Bartolomucci et al., 2005; Barnum, Blandino, & Deak, 2008), this could be important for a number of behavioral tests relevant for schizophrenia, such as social interaction.

A logical starting point for study of the effects of maternal stress on brain development in the offspring is the fetus. Compared with work on adult offspring, however, far less has been done on the question of how various parts of the fetal brain are altered in the early, critical stages of development. It is known that maternal stress during the last week of gestation in the rat elevates circulating GC and catecholamine levels in the fetus (Weinstock, 2007). Maternal plasma free tryptophan is also elevated, which is associated with increased fetal brain tryptophan and serotonin (5-HT) (Peters, 1990). These increases are stable until at least postnatal day 10. Time course studies estimated that the critical period for maternal stress-induced changes in brain 5-HT neurons is between E15 and birth (Peters, 1989). Cross-fostering experiments also revealed, however, that the effects of maternal stress are strongly influenced by the postnatal rearing environment (Peters, 1988). In a paradigm that tests three different levels of severity of maternal stress just before birth, increases in neuronal activity, as assessed by cFos up-regulation, in the fetal paraventricular nucleus (PVN) of the hypothalamus were observed in direct relation to the amount of increase in maternal corticosterone (Fujioka et al., 2003). In the more severe stress condition, more apoptotic cells are apparent, and corticotrophin releasing hormone (CRH) is decreased, as is the total length of PVN neuronal processes. It is interesting that it was reported that short duration, mild maternal stress has the opposite effect of strong stress: mild stress can enhance learning and LTP in adult offspring and increase neurogenesis and neuronal differentiation in the hippocampus of neonatal offspring (Fujioka et al., 2006). Another study reported that when maternal stress was applied during the last week of gestation, CRH and α-endorphin decrease in the fetal hypothalamus (Ohkawa et al., 1991). In contrast, a very short period of stress elevates CRH expression in the fetal PVN, and CRH+ neurons achieve a more mature morphology (Fujioka et al., 1999). Thus, it appears that a brief period of maternal stress may stimulate differentiation, whereas more chronic or severe stress is toxic to the fetal PVN (see figure 13.2).

It is therefore interesting that maternal stress activates epinephrine and norepinephrine (NE) neurons that stimulate CRH+ neurons in the PVN. Moreover, maternal Dex injection enhances the maturity of fetal NE neurons and their projections and induces expression of the NE transporter (Owen, Andrews, & Matthews, 2005). CRH receptors in the adult offspring cortex are elevated over those of controls, and spine frequencies and dendrite complexity in layer II/III pyramidal neurons of the anterior cingulate and orbitofrontal cortex are reduced. Serotonergic neurons also directly innervate and stimulate PVN CRH+ neurons. Maternal injection of Dex promotes 5-HT transporter development and increases hypothalamic 5-HT levels (Owen, Andrews, & Matthews, 2005). Maternal stress also induces a chronic astroglial reaction in adult offspring, which could be indicative of inflammation (Barros et al., 2006). If so, it would be a key finding. However, another study reported a reduction in hippocampal S100B, an astrocyte protein (Van den Hove et al., 2006). Synthetic GC promotes early maturation of dopamine (DA) and altered γ-aminobutyric acid (GABA) systems in the forebrain of adult rat offspring (Owen, Andrews, & Matthews, 2005). An altered inhibitory pathway is also suggested by the finding that infant and adult male offspring of stressed dams display an increased rate of kindling-induced seizures (Edwards et al., 2002). In a human study, the offspring of pregnant women treated with Dex score higher than normal on tests of emotionality, avoidance, and shyness (Trautman et al., 1996).

A typical feature of maternal stress is that the adult offspring do not regulate glucocorticoid receptor (GR) expression properly in response to increased GC. That is, there is reduced feedback in the HPA axis. Although studies of adult rat offspring have produced mixed results regarding specific changes caused by maternal stress, the data have consistently shown that induced changes in HPA axis activity are correlated with abnormalities in hippocampal negative feedback. In fact, the feedback inhibitory control is altered even in the affected fetus. In a study of fetal responses to maternal Dex injections from E17–E19, no downregulation of GRs was found in the forebrain (Slotkin et al., 2008). Another interesting observation is that late, brief maternal restraint stress decreases fetal pH, which is consistent with a hypoxic condition. In a further parallel with hypoxia, fetal plasma corticosterone and ACTH are increased (Fan et al., 2009). This provides a link to another risk factor for schizophrenia: obstetric complications in late pregnancy (see chapter 3, this book).

The amygdala perceives threats such as stressors, and through its connections with the hypothalamus it stimulates the HPA axis. The amygdala is altered in the adult offspring of stressed dams (Weinstock, 2007). The lateral nucleus is larger, with more neurons expressing nitric oxide synthase. There are also differences in the number of neurons and glia in the basolateral, central, and lateral nuclei in male offspring, and there is an increase in CRH expression in the central nucleus, as well as decreased GRs in the hippocampus (Mueller & Bale, 2008). The levels of CRH are elevated in the amygdala of the male offspring, which is relevant for their increased emotionality (Cratty et al., 1995). Cytokines of the bone morphogenetic protein (BMP) family may play a role in mediating the effects of maternal stress on the amygdala. Smad-1 transduces signaling of several BMPs, and its expression in the lateral and basolateral nuclei of the amygdala is increased in the offspring of stressed rats, whereas its response to stress in those offspring is blunted (Kaur & Salm, 2008). Further work will be necessary to assess whether BMPs are involved in the maternal stress-induced structural changes in the amygdala and the altered fear responses mediated by the amygdala.

The hippocampus displays a remarkable degree of functional and structural plasticity in response to maternal stress and GCs. There is an altered immediate early gene response to adult stress (Mairesse et al., 2007; Viltart & Vanbesien-Mailliot, 2007), which is consistent with reduced GR expression. Expression of the postsynaptic protein, homer, is altered by maternal stress (Ary et al., 2007). There is a report of reduced 5-HT transporter expression in hippocampal CA1, as well as increased levels of 5-HT receptors (Peters, 1990), both of which could underlie a greater sensitivity to citalopram, a selective 5-HT uptake inhibitor used in several assays of depressive-like behavior. A more recent study found, however, that 5-HT1A receptor levels are decreased in the region of the hippocampus involved in emotion (ventral hippocampus) but unchanged in the region involved in learning (dorsal hippocampus). Expression of 5-HT2A is not altered in either area (Van den Hove et al., 2006). Synthetic GC administration increases hypothalamic 5-HT levels and reduces 5-HT turnover in the hippocampus (Owen, Andrews, & Matthews, 2005).

Given the long-standing DA hypothesis of schizophrenia, it is important to consider the effects of maternal stress on this transmitter pathway. Positron emission tomography (PET) of young adult monkeys born to stressed mothers suggests lower DA decarboxylase and up-regulation of D2 DA receptors in the striatum. Moreover, these changes are correlated with fearful and stereotypic behaviors (Roberts et al., 2004). In contrast, down-regulation of D2 receptors is seen in the striatum of adult male mouse offspring following prolonged maternal stress. The latter study also reported increased DA turnover in striatum and lower levels of the DA transporter in both striatum and substantia-ventral tegmentum area (Son et al., 2006). In rat offspring, DA turnover is increased in female offspring, while 5-HT turnover is decreased in male offspring. In freely moving adult rat offspring of stressed dams, both basal and intraperitoneal amphetamine-induced stimulation of DA and NE output in the nucleus accumbens is higher than in controls (Silvagni et al., 2008). Increases in D2 and N-methyl-D-aspartate (NMDA) receptors in the medial and dorsal prefrontal cortices, the nucleus accumbens, and hippocampal area CA1 are found in male offspring (Henry et al., 1995; Weinstock, 2007). Moreover, phosphorylation of NMDA receptor subunits NR1 and NR2B in the prefrontal cortex in response to acute stress in adulthood is attenuated in male offspring of stressed dams (Fumagalli et al., 2009). This could be part of the molecular basis for altered feedback inhibition in the HPA stress response. It is clear that NMDA- and AMPA (2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid)-mediated currents regulate synaptic potentiation and learning by way of GRs (e.g., Yuen et al., 2009). Regarding the relevance of D2 receptor up-regulation for schizophrenia, meta-analyses have concluded that D2 density may be only slightly elevated in the striatum of a subset of patients (Howes et al., 2009). Nonetheless, several of the observations on DA, coupled with the changes in relevant DA-mediated behaviors, can be interpreted as being consistent with a hyperdopaminergic state in schizophrenia. Ultimately, the most relevant comparisons with the human studies would be with D2 receptor occupancy and DA release in the animal striatum.

Maternal stress in rhesus monkeys decreases neurogenesis in the dentate gyrus and synapse number in the hippocampus of adult offspring, and there is a 10% decrease in hippocampal volume (Coe et al., 2003). Maternal Dex administration also reduces cell proliferation in the dentate gyrus of neonatal offspring (Tauber et al., 2006). Maternal stress in rats causes an accelerated decline in hippocampal neurogenesis with age, which is accompanied by a decrease in granule cells and is correlated with a deficit in learning in the water maze. Unlike the case with controls, there is also a failure to increase production of new neurons with training in the maze (Lemaire et al., 2000; Koehl et al., 2009). Maternal administration of Dex also reduces hippocampal size (Uno et al., 1990), and maternal stress reduces the number of granule neurons in the dentate gyrus of female rat offspring (Weinstock, 2007). In rats bred for high—but not for low—anxiety, maternal stress reduces postnatal neurogenesis in the hippocampus (Lucassen et al., 2009). Maternal stress in the rat also decreases incorporation of the cell proliferation marker, BrdU, in the fetal hippocampus and nucleus accumbens (Kawamura et al., 2006). In a human study, adult neural stem cell proliferation apparently is decreased in schizophrenia but not in depression (Reif et al., 2007).

Another putative risk factor for schizophrenia is maternal iron deficiency, which is mechanistically linked to two other such risk factors, fetal hypoxia and nutritional deprivation (Insel et al., 2008). Iron-deficient infants and children display motor and cognitive deficits in common with children who later develop schizophrenia. Moreover, iron deficiency affects aspects of the brain that are altered in schizophrenia, such as DA transmission and myelination. Thus, it is of interest that mild stress during pregnancy in monkeys results in offspring that are more vulnerable to developing iron deficiency anemia between four and eight months of age (Coe et al., 2009). Although the mechanism of this phenomenon is not yet known, it is likely that there is diminished transfer of iron from the mother to the embryo during gestation. When stressed mothers and offspring are maintained under limited iron in the diet, the one-year-olds display lower DA and higher NE levels than controls raised on the same diet.

Much of the work on the mechanism of how maternal stress alters fetal development has been devoted to the role of the HPA axis (figure 13.1). This is largely because GC secretion is a key biological response to stress, and this hormone can exert profound effects on brain development. A particular target of GCs is the hippocampus, which expresses the highest levels of GRs in the brain. It is clear that the increase in maternal GC induced by maternal stress plays a major role in subsequent reactions to stress by the adult offspring. This was shown directly by experiments in rats in which GC levels in the dam were controlled by adrenalectomy followed by implantation of a pellet that released basal levels of GCs. Subcutaneous injection of GC was then used to increase its level to that seen in maternal stress. The adult offspring were tested for their stress response by measuring the GC response to restraint stress. The positive control yielded the expected results; raising GC levels in adrenalectomized dams up to the levels seen with maternal stress results in a normal, prolonged GC induction by stress in adult offspring as well as decreased GR levels. In contrast, the offspring of dams that were stressed, but whose GC levels were maintained at basal levels, do not display the expected, prolonged GC response to restraint stress as adults. Moreover, these offspring do not display the normal decrease in hippocampal GRs (Barbazanges et al., 1996). Maternal adrenalectomy before stress also abolishes anxiogenic behavior and spatial memory deficits in the offspring (Zagron & Weinstock, 2006). In addition, maternal GC pellets increase GC levels, locomotor activity, and basal DA metabolism in the offspring (Fumagalli et al., 2007). In a similar manipulation, maternal ACTH administration can also mimic some of the behaviors induced by maternal stress. It will be critically important to use direct manipulations of GC levels to test if other behavioral deficits, as well as the neurochemical and neuropathologic abnormalities observed in maternal stress, are also controlled by maternal GC.

There are, however, some issues in applying this model to humans. For instance, the maternal GC response to stress decreases significantly during human pregnancy, becoming rather low by late pregnancy. Thus, at a time when there appears to be the strongest link between maternal and fetal GC levels, the maternal HPA axis is less sensitive to stress (Talge, Neal, & Glover, 2007). It is interesting that the maternal emotional state is very rapidly reflected in fetal behavior and heart rate, which is not easily explained by the slower responses of the HPA axis (Talge, Neal, & Glover, 2007). This rapid response could be mediated by the known activation of the sympathetic nervous system by stress, and unmetabolized NE can cross the placenta. Another indication for a role for catecholamines is the finding that the expected spatial learning deficits can be prevented by administration of the α-adrenergic receptor blocker, propranolol, to the pregnant rat during stress.

Cytokines may also be relevant, as physical stress such as immobilization or inescapable tail shock can increase interleukin-1 (IL-1)α in the brain, and central administration of an IL-1 receptor antagonist prevents stress-induced changes in behavior as well as altered NE, DA, and 5-HT release and plasma ACTH levels (Plata-Salaman et al., 2000). In pregnant women, stress increases plasma tumor necrosis factor (TNF)-α and IL-6, while decreasing IL-10 (Coussons-Read, Okun, & Nettles, 2007). In pregnant mice, maternal stress reduces progesterone, which influences cytokine expression in the blood and decidua (Joachim et al., 2003; Blois et al., 2004). Unfortunately, little is known about cytokine changes in the fetal brain induced by maternal stress. It is likely that such alterations occur, as they do in the related syndrome of maternal immune activation (Patterson, 2009; chapter 10, this book).

The placenta is another important candidate tissue for mediating the effects of maternal stress on the fetus. This is particularly true for the early pregnancy stress paradigm, in which stress is administered before the fetal brain has developed. The placental connection to GCs is particularly important because these hormones regulate placental size, histology, blood flow, and nutrient transporter and hormone expression (Fowden & Forhead, 2009). Moreover, a high percentage of maternal GC is inactivated by 11α-hydroxysteroid dehydrogenase type 2 (11ßHSD2) in the placenta. This enzyme normally protects the fetus by breaking down the hormone, but its level is reduced by maternal stress (Darnaudery & Maccari, 2008). Thus, in many species, fetal GC concentrations parallel maternal levels during stress (Fowden & Forhead, 2009). Although maternal injection of Dex, which is not degraded by 11ßHSD2, is very effective in inducing altered behavior in the offspring, late-gestation Dex treatment increases the glucose transporters (GLUTs) 1 and 3 in the placenta (Langdown & Sugden, 2001). The latter observation is inconsistent with findings that maternal stress in late gestation reduces placental 11a-HSD2 and GLUT1 expression (Mairesse et al., 2007). The GLUT1 reduction is also obtained by genetically deleting 11ßHSD2 (Wyrwoll, Seckl, & Holmes, 2009). Moreover, another synthetic GC, triamcinolone, downregulates GLUT1 and 3. Inhibition of 11ßHSD2 during gestation produces permanent alterations in the HPA axis and anxiety-like behavior in the offspring (Welberg, Seckl, & Holmes, 2000). In a different paradigm, a failure to increase placental 11ßHSD2 after maternal stress is correlated with decreased neurogenesis in the adult offspring (Lucassen et al., 2009). Overall, these observations support the hypothesis that 11ßHSD2 protects the fetus from sharp increases in maternal GC such as those that occur during maternal stress. Nonetheless, maternal stress does increase GC levels in the fetus, at least during the final week of gestation in the rat. It is also interesting that another putative risk factor for schizophrenia, maternal malnutrition (see chapter 2, this book), reduces the activity of this enzyme (Fowden & Forhead, 2009), suggesting the possibility that some of the effects of malnutrition could be mediated by maternal GCs.

In the early maternal stress model in mice, placentae of male fetuses exhibit increased levels of peroxisome proliferator-activated receptor (PPAR)α, insulin like growth factor binding protein (IGFBP)-1, GLUT4, and hypoxia-inducible factor 3a. In contrast, female placentae display a reduced PPARα and IGFBP-1 (Mueller & Bale, 2008). PPARα expression is relevant because it regulates many cellular processes during development and is responsive to GC levels. It also regulates IGFBP-1. Given that methylation is critically important in models of postnatal stress, it is of interest that expression of DNA methyl transferase 1 (DNMT1), an enzyme involved in maintenance of methylation, is significantly lower in normal male placentae than in female placentae. Moreover, maternal stress appears to increase DNMT1 in female placentae more than in male placentae (Mueller & Bale, 2008). This suggests that the female placenta may be better able to maintain methylation under stress. In addition, hippocampal CRH and GR expression and methylation levels are altered by maternal stress in a sex-specific manner. The placenta also expresses CRH, and this is increased by GCs, unlike hypothalamic CRH expression, which is decreased by GCs (Robinson et al., 1988; King, Smith & Nicholson, 2001).

Catecholamines are important mediators of the maternal stress response, and the sympathetic nervous system plays a role in embryo implantation. Later in development, some of the maternal NE elevated by stress is not metabolized and constricts placental blood flow and glucose supply. It also activates the fetal HPA axis (Bellinger, Lubahn, & Lorton, 2008). Maternal NE is critical, as experiments with genetic deletion of DA decarboxylase suggest that NE crossing the placenta is required for survival (Thomas, Matsumoto, & Palmiter, 1995). Injection of NE into the third ventricle to stimulate the hypothalamus results in a prolonged increase in plasma GC in male but not female offspring of stressed dams. Thus, maternal stress affects activation of the HPA axis differently in male and female offspring (Reznikov, Nosenko, & Tarasenko, 1999).

Neurotrophins are secreted proteins that regulate synaptic plasticity in adulthood as well as many events during development, including neuronal survival and growth. Expression of some of them has also been found to be altered in schizophrenia. Thus, it is of interest that maternal stress results in reduced levels of brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (FGF-2) in the prefrontal cortex of adult rat offspring. In addition, BDNF and FGF-2 expression in these offspring responds very differently to stress in adulthood than it does in controls (Fumagalli et al., 2007). Alterations in neurotrophin levels could underlie some of the neuropathology as well as changes in neurogenesis observed in the offspring of stressed dams. Evidence for a role for GCs in mediating the inhibition of cell proliferation and neurogenesis in the hippocampus caused by stress in the adult is contradictory (Mirescu & Gould, 2006).

The level of postnatal maternal care strongly affects epigenetic regulation of GR expression in the hippocampus. Methylation of DNA upstream of the GR gene is altered by maternal care, and this determines the adult response to stress (Szyf, McGowan, & Meaney, 2008). Similar experiments are starting to be done in a mouse model of maternal stress. Adult male offspring of dams exposed to stress during early pregnancy (E1-7) exhibit reduction in methylation in the CRH promoter, which is correlated with increased CRH expression in the central nucleus of the amygdala. Conversely, there is an increase in methylation of the GR promoter that correlates with a decrease in hippocampal GR expression (Mueller & Bale, 2008). These findings are also consistent with increased GC levels in these offspring.

Work with nonhuman primates has revealed changes outside the nervous system that have relevance for behavior. For instance, almost all cells in the immune system have receptors for one or more of the hormones associated with the HPA axis, and mild maternal stress alters the immune system of the offspring (Coe & Lubach, 2005). In neonates, the proliferative response of mononuclear cells to antigens in vitro is deficient if the mother was stressed during late pregnancy, but it is greater than that of controls if the mother was stressed during early pregnancy. Administration of Dex during late pregnancy also decreases the response to antigens in the offspring. Maternal administration of ACTH reduces suppressor T cell activity measured in vitro in offspring that are one to two months old. These findings are consistent with the known ability of the HPA axis to modulate the immune system, and there is a moderate increase in cortisol levels in this monkey stress paradigm. On the other hand, ACTH does not cross the placenta at this stage, so action on the placenta is a possible intermediate mechanism. As already mentioned here, the placenta is a source of CRH, which can activate the fetal HPA axis to increase fetal GC levels (Challis et al., 2000). Natural killer cell activity is reduced in six-month-old offspring of stressed mothers, and at two years of age leukocytes display reduced proinflammatory responses to bacterial lipopolysaccharide in vitro. In a further indication of reduced immune status, maternal social stress lowers the level of maternal antibody in the newborn serum. This is important because the transfer of maternal IgG across the placenta during late pregnancy produces passive immunity in the infant against bacteria and viruses previously encountered by the mother. It is relevant that GCs can alter gut development, affecting the uptake of maternal immunoglobulin from the colostrum (Bellinger, Lubahn, & Lorton, 2008). Some of these changes in the immune system likely contribute to the greatly increased frequency of Shigella infections in these infants (Coe & Lubach, 2005). Altered immunity could also contribute to the observed changes in the species composition of commensal enteric bacteria in these animals. All of these phenomena are relevant for behavior because infection alters behavior, and there are striking changes in the both the immune system and the expression of immune-related molecules in the brains of schizophrenic subjects (Patterson, 2009).

In contrast to the status of the immune system in the monkey work, the picture with other mammals is mixed (Bellinger, Lubahn, & Lorton, 2008; Kohman et al., 2008; Merlot, Couret, & Otten, 2008). A study on adult offspring of stressed rats provided evidence of an enhanced immune status: increases in natural killer cells and CD8+ cells, and elevated proliferative and interferon (IFN)-γ responses to the phytohemagglutinin antigen (PHA). Surprisingly, these effects are not seen in the young offspring (Vanbesien-Mailliot et al., 2007). The latter result may explain at least some of the conflicting data from other studies on young rodents. Laviola et al. (2004) reported that juvenile offspring of stressed dams exhibit an exaggerated drop in CD4+ cells in response to the immunosuppressant cyclophosphamide. The various laboratories that conduct these studies use different intensities and timing of maternal stress. In adult rats, at least, acute stress enhances immune function whereas chronic stress suppresses it (Dhabhar & McEwen, 1997). In terms of the mechanism for how immune cells are altered by maternal stress, it is interesting that peritoneal macrophages taken from adult offspring of stressed pregnant mice display reduced phagocytosis, which can be corrected by maternal injection of the opioid antagonist naloxone (Fonseca et al., 2005).

Although there appears to be only a single human study of immune function in the offspring of stressed mothers, its findings agree with some of the animal work. In a study of healthy adult women born to mothers who experienced a major negative life event during pregnancy, cytokines from peripheral blood mononuclear cells were measured following PHA stimulation (Entringer et al., 2008). An elevation of IL-4, IL-6, and IL-10 without apparent change in IFN-γ suggests a bias toward T helper cell 2 (Th2) cytokine production. This is similar to findings with chronically depressed subjects. The women in this study, however, scored in the normal range in tests for depression and neuroticism, as well as in birth weight, postnatal care, and trauma experiences. Glucocorticoids can cause a shift from the Th1 to Th2 state, which favors humoral over cellular immunity. The Th2 bias is also similar to findings with maternal stress in mice (Pincus-Knackstedt et al., 2006), and adult offspring of stressed rats are reported to exhibit increased IL-10 and IL-6, although the results in various rat experiments are mixed, as already discussed here. If a bias toward a Th2 state is valid, there is a parallel with immune dysfunction in schizophrenia, where some reports have found evidence of such a bias in peripheral immune cells (Muller & Schwarz, 2008). Other consequences of a Th2 bias include increased susceptibility to atopic diseases such as asthma, eczema, and food allergies, as well as systemic lupus erythematosus.

Although the effects of maternal stress can be long-lasting, postnatal manipulations such as handling, environmental enrichment, treatment with a 5-HT reuptake inhibitor, or cross-fostering to a control dam can ameliorate or reverse many of these effects (Fox, Merali, & Harrison, 2006; Laviola et al., 2008). Cross-fostering reverses maternal stress-induced abnormalities such as increased fearfulness in the defensive withdrawal test (Qian et al., 2008), deficits in spatial learning and hippocampal type 1 GRs, and the prolonged GC response to novelty (Maccari et al., 1995; Brabham et al., 2000), as well as elevated D2 receptor levels (Barros et al., 2006). In one negative finding from a study using a different rat strain and method of maternal stress, cross-fostering had no effect on the social interaction deficit in males born to stressed dams (Lee et al., 2007). In the human literature, some studies have also distinguished effects on the offspring due to prenatal versus postnatal stress in the mother (Fumagalli et al., 2007; Talge, Neal, & Glover, 2007). The rescue of behavioral deficits by cross-fostering is particularly important, as it indicates that this procedure is necessary to determine which of the many effects of that maternal stress has on the offspring are due to prenatal rather than postnatal factors. Unfortunately, this has been done in only a small fraction of experiments. On the other hand, in the natural course of events, stress on the mother during pregnancy could continue to alter her later maternal behavior. Thus, using the same stressed dam to raise her litter is more relevant to the normal situation. It is primarily in mechanistic studies that cross-fostering becomes important.

The effect of environmental enrichment is of great interest from a therapeutic point of view. Providing adolescent offspring of stressed dams a larger cage with many novel objects, places to hide, and a running wheel almost completely reverses the deficit in play behavior and hypersecretion of GC in response to acute restraint stress (Morely-Fletcher et al., 2003); depressive-like behavior in the forced swim test and morphine-induced place behavior (Yang et al., 2006); and several parameters of immune status (Laviola et al., 2004). Moreover, housing the pregnant mouse in an enriched environment also significantly attenuates the effects of maternal stress on hippocampal cell proliferation and open field behavior (Maruoka et al., 2009). An important question is whether all of these effects of environmental enrichment could be explained by exercise on the running wheel (or adoption of a healthier lifestyle), which is the case for the effect of an enriched environment on adult hippocampal neurogenesis, for instance (Pereira et al., 2007). Early postnatal manipulation of the pups can also block the adverse effects of maternal stress on the survival of newborn cells as well as the number of immature and differentiated new neurons in the hippocampus (Lemaire et al., 2006). In this case, rat pups were removed to a clean cage with a heating lamp for 15 minutes a day, from birth until weaning. Although this treatment is termed handling, it can also be seen as a less severe form of the maternal separation stress paradigm. Nonetheless, this handling procedure has very positive effects on neurogenesis.

While the striking success of these various postnatal manipulations in blocking (or reversing) the effects of maternal stress is encouraging from the therapeutic point of view, the results also raise several provocative questions. Does the success of the seemingly very diverse postnatal manipulations of the environment suggest that the maternal stress model lacks robustness? Does it highlight the extreme poverty of the typical home cage environment? The early postnatal environment of the typical human is vastly more enriched than the typical laboratory animal, and the experience of a woman during what we would term a stressful pregnancy would seem to be far less harsh than that used in the physical stress applied to laboratory rats. Would we then expect that laboratory animals exhibit far more severe and irreversible symptoms than those expected for humans? The problem with these questions is that it is extremely difficult to compare the human brain’s response to psychologic stress, and the human symptoms of depression or schizophrenia, to those in laboratory animals, especially rodents.

Given that the maternal stress model has face validity for depression, several groups have tested antidepressant medications in this paradigm. Chronic administration of the tricyclic imipramine to adult offspring of stressed dams completely reverses their increased immobility in the forced swim test, as well as their elevated 5-HT1A mRNA expression in the frontal cortex (Morely-Fletcher et al., 2004). Postnatal administration of the selective 5-HT uptake inhibitor fluoxetine normalizes the increased GC response to restraint stress, the 5-HT turnover in the hippocampus, and the decreased dendritic spine density and synapses on CA3 pyramidal cells, and partially restores learning in the water maze test (Ishiwata, Shiga, & Okado, 2005). Tianeptine, which unlike other antidepressants, increases neuronal 5-HT uptake, reduces immobility in the forced swim test (Morely-Fletcher et al., 2003). A recent study compared several antidepressant drugs and found that imipramine, fluoxetine, tianeptine, and mirtazapine all decreased immobility time in the forced swim test, increased time in the center of the open field, and lowered stress-induced plasma GC and hippocampal GR levels (Szymanska et al., 2009). These results with drugs of various known mechanisms of action further confirm the face, construct, and predictive value of the maternal stress model for depression. One surprising result of this study is that GC and GR levels are elevated in the offspring of stressed dams, which is inconsistent with the lack of GC feedback inhibition during HPA axis hyperactivity. The finding is, however, consistent with known GC-driven hippocampal atrophy.

Neuropeptides have also been used to reverse abnormal behaviors in offspring of stressed dams. The deficits in social interaction displayed by such offspring suggest that there could be an alteration in the neuropeptide systems that regulate this behavior. Oxytocin is one such peptide that is expressed in the PVN and activates neurons in the central nucleus of the amygdala, promoting social behavior (Huber, Veinante, & Stoop, 2005; Hammock & Young, 2006). Thus, it is of interest that adult male offspring of stressed dams display a deficit in oxytocin expression and an increase in oxytocin binding in that nucleus in the amygdala. Moreover, injection of this neuropeptide into the central amygdala during a 10-minute behavioral testing period enhances social interaction in these offspring in a dose-dependent manner (Lee et al., 2007). Controls included injection of saline and vasopressin. This experiment is important for understanding the mechanism of how maternal stress alters a behavior and has clear relevance to social withdrawal in schizophrenia.

An intriguing question is whether animal models of maternal stress exhibit more features of major depression or schizophrenia. Certainly the adult offspring exhibit clear features of depression: early immobility in the forced swim test, alleviated by antidepressant drugs; enhanced emotionality; vulnerability to drugs of abuse; circadian disturbances; and an activated HPA axis. These symptoms are also shared with schizoaffective disorder, with its combination of mood disorder coupled with features of schizophrenia. There is also a significant body of evidence that schizophrenia is associated with elevated and pharmacologically induced HPA axis activity. Moreover, antipsychotic drugs reduce HPA axis activity (Walker, Mittal, & Tessner, 2007). Hippocampal volume is also reduced early in schizophrenia, which could be a sign of elevated GC toxicity. There is some evidence of reduced GR expression and increased pituitary volume as well, suggesting dysfunction in the HPA axis feedback system (Walker, Mittal, & Tessner, 2007; Takahashi et al., 2009). Although there appear to be some similarities with regard to these HPA-related phenotypes in schizophrenia and major depression, there are clearly many differences, including the presence of positive symptoms such as hallucinations and delusions, which occur only rarely in major depression. Until experimenters overcome the obstacles of assaying these symptoms in animals, however, it will be difficult to define animal models such as maternal stress more precisely using behavioral criteria. On the other hand, there are neurochemical features of the maternal stress offspring that are consistent with schizophrenia, and it may be highly informative when the most common neuromorphologic finding in schizophrenia, enlarged ventricles, is examined in this model.

Thanks to Elaine Hsiao for the figures, and for her and Alan Brown’s helpful comments on the manuscript, and to Laura Rodriguez for editing assistance.

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