Puberty and schizophrenia onset

Abstract

Estradiol, the derivative of estrogen that is most active in the brain, protects brain function in a variety of ways. There is evidence that estradiol exerts a positive effect on neuron viability. Though this may not cause an increase in the ultimate number of adult neurons, even a temporary effect may facilitate neuronal connectivity (Purves 1985). Estradiol also enhances neuron growth (Torand-Allerand 1984). Furthermore, estradiol may act independently by altering growth-related genes directly or may act in concert with growth factors (neurotrophins) and their receptors (Toran-Allerand 1996). Woolley and McEwen (1992; 1994a) have repeatedly demonstrated that estradiol enhances synaptic density. In 1992, they reported that synaptic density in the hippocampal CA1 region in the adult female rat was sensitive to estradiol and correlated with levels of ovarian steroids over the 5-day estrous cycle. In a 24-h period when estrogen levels dropped, hippocampal synaptic density decreased by 32%. They further demonstrated that estrogen treatment increased the density of dendritic spines on pyramidal neurons in the hippocampus by 35% (Woolley et al. 1997). Female sex hormones have long been known to affect the pace of myelination (Petropoulos et al. 1972). Failure of myelination to occur in a timely manner during adolescence may result in increased vulnerability to brain pathology (Benes 1989). Furthermore, estrogen seems to protect vulnerable hippocampal neurons from glucose deprivation (Bishop and Simpkins 1995; Goodman et al. 1996). Estrogen acts as an antioxidant, thereby preventing free radicals from fracturing membrane lipids, proteins, and DNA and leading to cell death. Glutamate and β-amyloid are two such toxins that produce free radicals and whose detrimental effects can be attenuated by estrogen (Behl et al. 1995; Goodman et al. 1996). Estrogens also affect a variety of neurotransmitter systems. The system most commonly associated with schizophrenia is dopamine (DA). Other relevant neurotransmitters modulated by estrogen include serotonin, glutamate, and acetylcholine. Häfner et al. (1991) suggest that estrogen exerts a potent antidopaminergic effect, thereby raising the vulnerability threshold for psychosis in women. In ophorectomized/castrated neonatal and adult rats, they examined the effects of gonadal hormones, estradiol and testosterone, on behavioral changes (catalepsy) induced by the DA antagonist haloperidol and by the DA agonist apomorphine (oral stereotypies, grooming, and sitting behavior). Estradiol attenuated the behavioral changes induced by both haloperidol and apomorphine. This indicated downward regulation of DA neurotransmission by estradiol, a finding which was confirmed by a follow-up ligand binding investigation showing that estradiol pretreatment significantly reduced DA-receptor affinity to striatal 3H-sulpiride binding (Häfner et al. 1991). DiPaolo and her co-workers have extensively studied the relationship between estradiol and dopamine in rat models. In line with the findings of H äfner et al., they have consistently found that the density of dopamine uptake sites of estradiol-treated rats increases by approximately 20% (DiPaolo et al. 1981; Levesque and DiPaolo 1989; 1991; Morisette and DiPaolo 1993a, b). They suggest that estrogens behave in opposition to dopamine: estrogens decrease dopaminergic transmission and induce a compensatory increase in the number of dopamine binding sites. They have also shown that striatal dopamine uptake site density fluctuates during the female estrous cycle: binding site density increases as estrogen levels climb (Morisette and DiPaolo 1993). With respect to other neurotransmitters, Fink et al. (1996) have shown that estradiol modulates the serotonergic (5-HT) system. They suggest that positive psychotic symptoms may result from abnormal dopaminergic activity, whereas negative symptoms may result from abnormal 5-HT function. © 2005 Springer-Verlag/Wien.