Schizophrenia
In schizophrenia, retrospective studies have suggested that head circumference is decreased at birth and developmental delays are present in early childhood, both of which implicate prenatal and early postnatal alterations in forebrain development (Cannon et al., 2002). The occurrence of prodromal symptoms in the majority of cases (Hafner et al., 1994), as well as the presence both prior to and after onset of illness of neuropsychological deficits (Crespo-Facorro et al., 2007) also implicates disruption of forebrain development. Neuropsychological dysfunction implicates the PFC in patients with schizophrenia, the cortical region that has expanded most extensively in mammalian evolution and that has been suggested to rely on key evolutionary developments in stem cell function (Martinez-Cerdeno et al., 2006).
Altered hippocampal development has also been implicated in the pathogenesis of schizophrenia (Kobayashi, 2009). Total brain gray matter and hippocampal volumes are reduced at the time of first episode in schizophrenia (Ohnuma et al., 1997; Gur et al., 1999) and at times later in the disease course, volume reductions have been observed in PFC, hippocampus and temporal lobe (Shenton et al., 2001). Longitudinal studies with structural imaging show that both the PFC and the medial temporal lobe become progressively smaller during the period when psychosis develops and that dorsal prefrontal regions experience even more loss as illness progresses, consistent with a neurodegenerative process (Pantelis et al., 2007). Post mortem studies of the cerebral cortex of patients with schizophrenia have shown reductions in neuropil (Selemon et al., 1998), as well as in GABAergic cells expressing PV and reelin (Guidotti et al., 2000; Fatemi et al., 2001; Hashimoto et al., 2008). Post mortem analysis of the hippocampus also shows evidence for an abnormal GABAergic system and suggests that important signaling pathways are altered, including WNT and TGFbeta (Benes et al., 1998, 2007; Todtenkopf and Benes, 1998; Arnold et al., 2005). While these post mortem findings may reflect changes in the adult brain due to disease progression and medication effects, alterations in cortical neurodevelopmental processes could also create vulnerabilities that develop later in life.
Genes that are implicated in stem cell regulation, including neuregulin, disc-1, wnt related genes, bdnf and fgfr1, have been associated with schizophrenia in genetic association and post mortem studies, suggesting NSCs dysregulation in at least some cases. Mouse models lacking fgfr1 embryonically have smaller hippocampi and cortical interneuron deficits similar to those in patients with psychosis (Ohkubo et al., 2004). Similarly, deficient bdnf, neuregulin and disc-1 genes in mice mimic various aspects of the disorder (Ayhan et al., 2009; Brandon et al., 2009; Meyer and Morris, 2009). Conversely, mutations found in some patients with schizophrenia have significant effects on cortical stem cell development. Mice lacking the genes within the 22q11 mutation (velocardiofacial syndrome, a known chromosomal abnormality predisposing to schizophrenia) have abnormal neurogenesis, specifically affecting upper cortical layers (Meechan et al., 2009). As in autism, patients with schizophrenia are likely heterogenous, with pathology in some determined by a component of neuronal functioning that arises postnatally and in others, determined by earlier disruptions of patterning and neurogenesis.