Autism
The brain structure of patients with autism spectrum disorders (ASD) including autism, Asperger's Disorder (AD) and pervasive development disorder not otherwise specified (PDD-NOS) has been found to be abnormal using several different approaches. It is now widely believed that at least some of the deficits are present very early in life and that abnormal embryonic brain development may be a contributor to later structural deficits.
The head circumference of some patients with autism has long been known to be larger (Davidovitch et al., 1996; Woodhouse et al., 1996; Fombonne et al., 1999; Miles et al., 2000) because of abnormal acceleration in growth in early infancy (Courchesne et al., 2003). While no studies have been published on the neuroanatomy of high-risk individuals before a diagnosis of autism is made, retrospective data have shown that children with macrocephaly and autism do not have increased head circumference at birth (Lainhart et al., 1997; Courchesne et al., 2003; Dementieva et al., 2005; Redcay and Courchesne, 2005) but begin to show larger head measures at about 4 months of age (Gillberg and de Souza, 2002; Courchesne et al., 2005; Redcay and Courchesne, 2005). These findings suggest that autism may be underlain by either problems in early postnatal life and/or processes of embryonic development on which these postnatal events depend. Structural imaging of individuals with autism has shown that differences in brain volume, including both white and gray matter, diminish after the age of 5 years (Hazlett et al., 2005), although some studies have reported increases in gray matter volume in adolescents and adults with ASD (Lotspeich et al., 2004; Palmen et al., 2005; Hazlett et al., 2006), particularly in PFC (Mitchell et al., 2009).
Although there is no clear mechanism accounting for the dysregulation in the trajectory of brain growth in ASD, one hypothesis stipulates that it is the consequence of altered regulation of neural stem cell proliferation or differentiation arising before birth (Vaccarino et al., 2009). Further evidence that early embryonic developmental events are implicated in the pathophysiology of autism comes from post mortem studies demonstrating a fundamental change in cortical structure. Patients with autism were shown to have an increased packing density of mini-columns, which are vertical (radial) assemblies of neurons thought to be anatomically and functionally interconnected (Casanova et al., 2003, 2006).
Several underlying mechanisms could explain macrocephaly and minicolumn pathology, all based on altered embryonic cortical development (Figure 3). The first is an increase in the number of radial units in the embryonic cerebral cortex, which in turn is thought to depend upon an increase in the number of “founder” NSCs in the cortical primordium (Rakic, 1995) (Figure 3). This mechanism is supported by the occurrence of mutations in pten, a gene that regulates embryonic stem cell proliferation (Eng, 2003) in a small number of autistic patients with macrocephaly (Butler et al., 2005). Abnormal expression of this gene in NSCs would likely result in an intrinsic alteration of stem cells. Interestingly, an animal model of pten mutations shows increased brain size and social deficits (Kwon et al., 2006), although this mutation was in differentiated neurons, not intrinsically affecting NSCs. In Fragile X syndrome, which frequently presents with symptoms of autism, fetal NSCs have been shown to differentiate into neurons at greater rates (Castren et al., 2005) and to misexpress multiple genes involved in proliferation and differentiation (Bhattacharyya et al., 2008). Mutant embryonic NSCs isolated from mice lacking the fragile X mental retardation protein (FMRP) due to a deletion in the fmr1 gene differentiate in greater numbers into immature neurons (Castren et al., 2005). These findings are similar to those obtained in Drosophila germline stem cells lacking an ortholog of the fmr1 gene (Yang et al., 2009). Thus, the pten and fmr1 mouse models of ASD support the hypothesis that an intrinsic abnormality in NSC is responsible for features of these disorders. Two members of the TF-II family of transcription factors involved in Williams syndrome, another disorder with abnormal social behavior, have been shown in mice to regulate specific gene targets that may be involved in embryonic stem cell differentiation (Makeyev and Bayarsaihan, 2009).
Figure 3  Two neuronal cell types, excitatory (blue) and inhibitory (red), contribute to minicolumn structure and functional balance in cortex. Autism associated genes play roles in the processes underlying the generation and migration of these cortical neurons. The disruption of these genes may determine some cortical abnormalities in autism. GABA interneurons surround each minicolumn, and some genetic evidence and post mortem data suggest a GABAergic abnormality in ASD (Fatemi et al., 2002). Multiple genes involved in the development and function of the GABAergic system, including dlx5, have been involved in Rett syndrome, a developmental abnormality with autistic features (Horike et al., 2005); furthermore, alterations in the development of GABAergic neuron circuitry have been found in mice lacking the Methyl-CpG binding protein 2 (MeCP2) gene, whose mutations are responsible for Rett syndrome (Medrihan et al., 2008; Zhang et al., 2010). Lastly, a large number of synaptic-related genes have been implicated in small subsets of patients with ASDs (in total, accounting for probably less than 3–4% of the cases) (Buxbaum, 2009; Radyushkin et al., 2009). Thus, it appears that abnormalities in both the early-determined size and scaffolding of the cerebral cortex and later developing synaptic connections may play a role in individual cases of autism.