Autism spectrum disorders: developmental disconnection syndromes
Introduction
Autism spectrum disorders (ASDs) form a heterogeneous, neurodevelopmental syndrome for which there is yet no unifying pathological or neurobiological etiology. It is defined by clinical assessment and onset of three core disturbances before three years of age: atypical social behavior; disrupted verbal and non-verbal communication; and unusual patterns of highly restricted interests and repetitive behaviors. However, across these core features there are significant differences in the extent and quality of symptoms; for example, although language problems are fundamental, delay in spoken language is observed in only half of ASD subjects [1, 2]. Other associated, but non-core, features such as mental retardation are also variable, and current data suggest that <50% of all individuals who have autism present with significant cognitive impairment [3]. Social impairments can also be expressed in different ways — some individuals who have ASD display an aloof style of social interaction, whereas others actively seek personal interactions, albeit in a socially odd manner [4, 5]. Similarly, although onset before age three is mandatory in the current diagnostic scheme, there also are major differences in developmental course, with some children manifesting signs of the disorder from early infancy and others experiencing behavioral regression in the second or third year of life. Finally, as might be predicted from the clinical picture, treatment responsiveness also varies significantly among children with autism, and two children who appear the same at age three can show markedly different developmental trajectories at later ages.
If one considers this clinical heterogeneity, the lack of correlation between occurrence of different deficits (including the core features) [6], and also the genetic heterogeneity [7•, 8], it might be more constructive to think of ASDs as ‘the autisms’ than as a unitary syndrome (Figure 1). Thus, research efforts have the multiple goals of explaining the etiology of ASDs and of understanding the syndrome-specific and non-specific factors that influence the variability in relative risk, in developmental course of symptom expression, in treatment responsiveness and in co-occurrence of medical and mental health dysfunctions in ASDs [9].
Research into the biological and genetic basis of the autisms is in its infancy, so current etiological viewpoints are necessarily primitive. Here, we provide a synthesis of data published mostly in the past two years that support the emerging hypothesis that the autisms result from disconnection of brain regions that are highly evolved in humans and that are involved in higher-order associations [10, 11] (in other words, that ASDs form a ‘developmental disconnection syndrome’). This hypothesis is analogous to the concept of focal disconnection syndromes put forth 40 years ago by Norman Geschwind, in which disruptions in connectivity between higher association and multimodal cortical regions lead to specific disorders of cognition [12, 13]. However, owing to the developmental nature of the autisms, disconnection in the case of ASDs is not primarily a disruption of previously connected regions, as in the original disconnection syndromes, but rather is a failure of their normal development that might have diverse etiologies.
Thus, developmental disconnection in the ASDs could include a weakening of already formed connections, or a failure of certain connections to establish correct organization de novo. From a neurobiological perspective, the affected stages of development could include prenatally determined histogenic events such as neuronal migration and axon pathfinding, which establish proper positioning and patterning of basic connectivity, and postnatally regulated features of dendritic development, synaptogenesis and pruning. At these postnatal stages, even subtle disturbances in timing might influence connectivity and disconnectivity. Disrupting basic histogenic processes across an extended period of development and maturation in humans, which begins in utero and extends well into childhood [14, 15], provides an obvious point of convergence of interactions between genes and environmental factors that influence development. Studies in monkeys indicate that, although many developmental events such as neuron production and migration begin simultaneously across the cerebral cortex, differences in the duration of histogenesis between functional areas provide opportunities for differential disruptions that depend on the timing of the environmental insult [16]. For example, neurons that form agranular association cortices in frontal regions are produced and migrate to their destinations in two-thirds of the time needed to assemble primary sensory granular cortices.
Section snippets
Heritability of the autisms
Based on twin and family studies, the autisms are among the most highly heritable common neuropsychiatric disorders [17, 18, 19, 20]. The risk to a sibling born to a family in which there is already an autistic proband is estimated to be 25–100 times greater than the risk for the general population [21]. The severity of the three core disturbances varies across the autisms, but many of the core and associated features show familial clustering [1, 22, 23, 24] and evidence of heritability [25].
Limited clues regarding pathophysiology of the autisms
The histopathology of the cerebral cortex in the autisms as observed to date indicates that there is only minor disruption to the fundamental radial and tangential organization of neurons and glia [27]. There are reports of altered packing density of cells, minor and highly variable disruption of dendritic orientation, reduced size and spacing of radial minicolumns of neurons in different cortical areas including the frontal lobe [28•, 29], and selective reduction in cell number in some
Intersection of the autisms with the development of functional connectivity
Recent basic neurodevelopmental studies have defined molecular mechanisms that regulate neuronal migration, axon pathfinding, synapse construction and synapse deconstruction, all of which contribute to the functional and structural connectivity that underlies higher cognitive functions. Perhaps most striking has been the discovery that the molecular systems involved in this complex process are plieotropic: the transcription factors, cell adhesion molecules, extracellular matrix proteins, axon
Linking neurodevelopmental etiology and the genetics of the autisms
Connecting the neurobiological components that build and modify connectivity to the genetic etiologies of the autisms remains a significant challenge, in part owing to moderate-to-weak genetic associations, the likely involvement of multiple genes, and the difficulties of replication in heterogeneous clinical populations [57]. It is becoming clear that the genetics of idiopathic autisms is complex, involving multigenic interactions and potentially multiple, rare genetic variants, or mutations.
Common risk alleles of autism candidate genes that influence connectivity
To explore the contribution of genes that regulate connectivity, Geschwind and colleagues performed an association study on a single, large cohort in which ∼35 genes are involved in axonal pathfinding and neuronal migration [62]. This demonstrated conclusive association of ASDs with the genes encoding Neurexins 1 and 3 (NRXN1 and NRXN3) and the GABA receptor β3 (GABRB3), and suggestive association with SLIT1 and with an overall significant over-representation of single-nucleotide polymorphisms
Conclusions
Moving from genes to modeling the autisms in experimental systems is challenging for several reasons. Here, we have explored only a few key developmental issues. First, the autisms are disorders in which complex information processing might be disturbed at different levels of development, introducing substantial heterogeneity. Fundamental to this core feature of the hypothesis is the detailed characterization of circuit development that is hierarchical, progressing from first-order pathways to
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Melanie May of the Vanderbilt Kennedy Center Graphics Department for producing Figure 2. PL acknowledges support from National Institutes of Health (NIH) grant MH65299, National Institute of Child Health and Human Development (NICHD) core grant HD15052, and the Marino Autism Research Institute (PL). DHG acknowledges support from the National Institute of Mental Health (NIMH) R01 MH64547, the UCLA STAART Center grant U54 MH68172 (Marian Sigman, PI), and the Cure Autism Now Foundation.
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