One important role for α7 nAChRs, in conjunction with α3-containing nAChRs, is the induction of the KCC2 chloride transporter in pyramidal neurons ( Liu et al., 2006). This transporter lowers the internal Cl− concentration of the neuron and changes GABA from a depolarizing to a hyperpolarizing or inhibitory

neurotransmitter. A specific role of α7 nAChRs was demonstrated by failure of the induction of KCC2 by treatment with α7 nAChR antagonists and in α7 KO mice ( Zhang and Berg, 2007). At the time of birth, α7 nAChRs are involved in the transformation of glutamate neurotransmission from primarily NMDA-type receptors to kainate-aspartate receptors. α7 nAChRs remain embedded in the glutamate receptor-containing postsynaptic density. Trametinib Cholinergic innervation of the hippocampus occurs near the time of birth; therefore, the endogenous ligand for fetal α7 nAChRs cannot be synaptically

Ruxolitinib released acetylcholine (Derrington and Borroni, 1990). A possible candidate is choline, which, in addition to its other development roles, activates α7 nAChRs at levels several fold higher than acetylcholine. Choline levels in human neonatal cord blood (∼35 μM) are three times higher than those in adult blood (Zeisel et al., 1980). These levels are sufficient to selectively downregulate α7 nAChRs on hippocampal neurons in tissue culture, perhaps reflecting a chronic low level of receptor stimulation (Alkondon et al., 1997 and Uteshev et al., 2003). Brief choline treatment during gestation is associated with increased excitability and dendritic development in hippocampal pyramidal neurons (Li et al., 2004). Choline is an essential dietary nutrient. Normally humans have adequate choline, but during pregnancy many women are thought to be deficient because the fetus makes large demands for use in the synthesis

of cell membranes (Meck and Williams, 2003). In addition to poor maternal diet, choline deficiency for the fetus can occur because of maternal stress, which leads the mother to sequester choline in her own liver. Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine isothipendyl and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia. Experiments in animal models suggest that choline supplementation during gestation and early postnatal development may produce a reversal of sensory inhibitory deficits that lasts through adulthood (Li et al., 2004). Clinical trials are currently in progress. In addition to genetic risk, exposure to nicotine, and dietary deficiency, maternal infection is a risk factor for schizophrenia (Patterson, 2007). In some cases the infectious agent enters the fetus, but in most cases, like influenza, it remains in the mother’s respiratory tract. It is the deleterious effect of her cytokine response to the infection on the placenta that appears to be pathogenic.