Many cellular mechanisms have the potential to contribute

Many cellular mechanisms have the potential to contribute to enlarged carboxypeptidase a size and to faulty connections among centers in the brain that are thought to be linked to abnormal behaviors in ASD. While neurite outgrowth and pruning normally occur during the time period in which the accelerated brain growth is observed in humans, they are not the only candidates capable of contributing to this phenomenon. We hypothesize that increased cortical cell numbers resulting from enhanced SVZ proliferation and, possibly, the greater self-renewal capacity of cortical progenitors could have a cascade effect on later downstream processes in development through a direct increase in neuronal numbers, as has been reported in autism (Courchesne et al., 2011), or indirectly through altered glial cell numbers (Herbert, 2005). These processes could then trigger abnormalities in connectivity resulting from altered lamination, neurite outgrowth (Courchesne et al., 2011; Stoner et al., 2014), or other processes. Our findings indicate that environmental factors such as mild maternal inflammation and subsequent alterations in the neural stem cell redox balance can significantly alter brain development in affected offspring and could set up a cascade of cellular changes that lead to brain overgrowth and abnormal behaviors in autism.
Experimental Procedures
Acknowledgments
Introduction New neurons are generated throughout adulthood, and at least two neurogenic regions in the adult mammalian brain have been identified: the subventricular zone lining the lateral ventricles and the dentate gyrus (DG) of the hippocampal formation (Braun and Jessberger, 2014). It has been recently reported that in humans, up to one-third of hippocampal neurons are replaced with newborn neurons over a lifetime, implying a functional importance for this process (Spalding et al., 2013). There is increasing evidence that adult neurogenesis plays a role in cognitive processes, and aberrant or decreased levels of neurogenesis have been associated with a number of neuropsychiatric and neurodegenerative diseases (Braun and Jessberger, 2014; Christian et al., 2014). Notably, adult neurogenesis is dynamically regulated, and the control over the number of newly generated neurons occurs at multiple stages (Ma et al., 2009). For example, physical activity such as voluntary wheel running has a robust positive effect on the number of dividing cells in the DG, whereas an enriched environment has been shown to promote survival of newborn neurons (Ma et al., 2009). Aging, on the contrary, is accompanied by a drastic reduction in the number of dividing cells in the brain in rodents as well as in humans (Christian et al., 2014; Knoth et al., 2010). However, the identification and in vivo tracking of neurogenic neural stem/progenitor cells (NSPCs) remains challenging, and no markers have been identified that uniquely label NSPCs (Christian et al., 2014). The difficulties of identifying stem cells has led to controversial results, as studies assessing the in vivo behavior of NSPCs depend largely on the criteria and markers used (Bonaguidi et al., 2011; DeCarolis et al., 2013; Encinas et al., 2011; Lugert et al., 2010; Suh et al., 2007). Thus, it remains unclear whether distinct behaviors of NSPCs within the DG reflect different stem cell populations or whether the cells are just in a different state. Therefore, there is a need for novel and more specific markers to identify NSPCs in the adult hippocampus. We have recently shown that SPOT14, a protein that is associated with lipid metabolic processes (Colbert et al., 2010; Cunningham et al., 1998), is specifically expressed in the subgranular zone (SGZ) of the DG in cells with radial and nonradial morphology, using GFP expression driven by the regulatory elements of the SPOT14 promoter (SPOT14 reporter mice). We have demonstrated that SPOT14+ cells are low-proliferating, neurogenic NSPCs, suggesting that SPOT14 could serve as a useful marker for NSPCs (Knobloch et al., 2013). However, the expression of endogenous SPOT14 protein and the response of SPOT14+ NSPCs to stimuli that influence neurogenesis remained unknown. Thus, we here established staining of endogenous SPOT14 to verify that SPOT14 reporter mice reflect endogenous protein expression and tested the effects of positive and negative regulators of neurogenesis on the behavior of SPOT14+ NSPCs in the adult hippocampus.