Some Promising Leads Into The Genetics Of Autism

Significant progress in the genetic and neurobiological understanding of PPDs related to autism, such as Rett syndrome and Fragile X, provides new models of pathogenesis that may shed some light on autism. For example, drawing a parallel between the clinical characteristics of Rett syndrome and autism, Zoghbi has proposed that autism may be due to a disruption in postnatal, or experience-dependent synaptic activity40. More specifically, she proposed that proteins involved in synapse formation and stability may be implicated in several PPDs. Similarly, Fragile X syndrome mutation 1 (FMR1), which causes a specific dysmorphic syndrome that is often associated with autistic features is more and more perceived as a disorder of the synapse (see Chapter 30). Indeed, it is now believed that FMR1 protein plays a key role in the regulation of dendritically localized mRNA where regulation of synaptic protein synthesis may influence synaptic structure, stability, and plasticity41.

Given the clinical and developmental communalities between these two developmental disorders and autism, it is possible that autism is also a disease of the synapse. Some evidence implicating proteins playing a critical role in synapse fate has been reported in the last few years. In two brothers, one with X-linked autism and the other with X-linked Asperger syndrome, Jamain et al. (2003) identified a mutation in neuroligins 3 and 4 (NLG3 and NLG4), two proteins implicated in synapse development42. In another large French family, it was reported that a mutation in NLG4 that leads to a premature stop codon causes both mental retardation and autism43. Although several studies have failed to detect any major mutations in these two genes44,45, it is possible that the few cases reported in the literature are rare examples of highly penetrant mutations which were revealed because of their co-existence with other genetic abnormalities that were not identified. In any case, these mutations underline the importance of synaptic integrity in autism and point to these two genes as potential players, in combination with other genes, in autism. A better understanding of the processes implicated in synapse development will help genetic research by constructing models for synapse development. These models will serve as a basis for choosing combinations of genes to be tested in an interactive genetic paradigm.


The complex clinical presentation of autism may be explained by a unifying model postulating an excess of glutamatergic excitatory synapses and/or a deficit of GABAergic inhibitory synapses46. This imbalance in favour of more excitable (more weakly inhibited) cortex is associated with less differentiated cortex, which is prone to epilepsy (observed in approximately 30% of autistic children), perceptual anomalies, atypical memory and cognitive style and motor stereotypy, and repetitive behaviour. This hypothesis, although difficult to prove directly in humans, is substantiated by several examples from animal models showing how the imbalance of the excitatory/inhibitory (E/I) inputs could lead to cognitive or perceptual anomalies reminiscent of autism manifestations. For example, recent investigations into the development of auditory systems in rat have shown that sound representation in the brain is determined during a 1-week critical period when the environmental auditory exposure will determine the "tonotopic map"47,48. Under some experimental conditions, such as continuous or modulated noise, the critical period will be either abruptly interrupted or indefinitely protracted leading in both cases to "noisy" cortical development, with proneness to epilepsy and possibly abnormal auditory experience. Other studies have shown that during development, the balance between excitation and inhibition governs the establishment of sensory system projections, including the onset of the critical period49. Another animal model, the GAD65 knockout mouse, shows how important the balance between glutamatergic to GABAergic inputs is to cortical development. Indeed, these animals do not develop binocular vision, an effect that is reversed by pharmacological enhancement of inhibitory activity50. Another example is provided by mice lacking the gastrin-related peptide receptor (GRPR). Normally, neurons with GRPR receptors enhance GABA activity, which keeps the glutamate activity under control in the amygdala. Contrary to wild-type mice that show extinction of fear reactivity to a conditioned stimulus that was previously paired to an unconditioned fearful stimulus, mice lacking the GRPR show no extinction of this conditioned fear51. This suggests that downregulation of GABA activity may be involved in the synaptic plasticity required for controlling adjustment to fear. More recently, it was determined that a mouse model characterized by a 50% reduction in GABAergic interneurons due to a knockout of the hepatocyte growth factor/scatter factor (HGF/SF) displays behaviours that are highly evocative of autism, with increased susceptibility to seizures, heightened anxiety, and diminished social interaction52. These examples illustrate the importance of experience-dependent and constitutive (E/I) inputs in the developing brain. It is possible that an imbalance in these inputs, due either to genetic anomalies or aberrant early environmental experiences, leads to highly excitable cortex and defects in the basic cognitive functions necessary to develop higher cognitive abilities.

In the autistic brain, altered neuronal connectivity may develop as a consequence of widespread alterations in synapse elimination and/or formation53. The timing of abnormal brain growth in autism in early postnatal development suggests defects in neuronal connectivity. The association with synaptic abnormalities is further strengthened by the fact that autistic behaviour is exhibited in fragile X syndrome, a disorder with a known genetic cause and substantial symptomatic overlap with autism. As discussed in more detail in Chapter 30, examinations of neuronal morphology in fragile X syndrome revealed specific structural alterations in the synapse (for review, see ref. 54). In particular, dendritic spines in specific cortical regions are abnormally long and thin. The decreased dendritic branching of hippocampal neurons of autistic patients further support a reduction in neuronal connectivity55. Studies on cerebral cortex in autism also indicate abnormalities in synaptic and columnar structure56,57 and neuronal migration58. Further, analysis of changes in brain size of autistic patients revealed that much of the brain overgrowth occurs postnatally within the first 614 months59, a period that coincides with rapid increase in synaptogenesis, dendritic arborization, and myelination60. Finally, anatomical analysis indicates that cortical areas most affected are those essential for complex cognitive functions such as attention, social behaviour, and language. However, additional work is necessary to characterize how defects in neuronal connectivity translate to abnormal behaviour associated with autism.


As discussed earlier, abnormalities in neuronal connectivity and altered E/I synaptic input in early postnatal development are thought to be associated with autism61. To understand how excitation and inhibition is maintained it is important to reveal how specific number of excitatory and inhibitory synapses is achieved. Alteration of the E/I ratio may result from abnormal function/expression of molecules that regulate the number and activity of synaptic contacts in early neuronal development62. To gain in-depth knowledge about the biology of autism, it will be important to define molecular factors involved in synapse formation, differentiation, and stability that are affected in autism. Chromosomal aberrations associated with autism that harbour genes implicated in the regulation of the E/I synaptic balance include members of the neuroligin family and the postsynaptic density protein (PSD-95) family (see Table 1; see also Chapter 7). It is worth mentioning that the genes coding for PSD-95 and neuroligin 2 are located in very close proximity on chromosome 17p13.142. This proximity may indicate that these two genes have common genetic mechanisms of regulation. These observations, combined with the identification of de novo mutations in genes coding for other members of the neuroligin family (neuroligins 3 and 4) in patients with autism42,43, suggest that abnormalities in the function of neuroligins result in synaptic imbalance and predisposition toward autism. These results are consistent with the model discussed earlier which proposes an altered E/I ratio in autism.

How do these proteins control synaptic balance? At the postsynaptic density, an electron-dense cytoskeletal structure beneath the plasma membrane of mainly glutamatergic excitatory synapses, neurotransmitter receptors, and signalling molecules are clustered and thereby poised to respond to synaptic stimuli63,64. Specific members of the neuroligin family, enriched at glutamatergic synapses, have been recently implicated in the development of synaptic contacts. Neuroligins bind to neurexins, neuron-specific cell surface proteins present at the presynaptic terminal, which are proposed to act as a nucleation site for coupling cell adhesion molecules to synaptic vesicle exocytosis62,65. At excitatory postsynaptic sites, neuroligins associate with PSD-95 and this interaction is thought to modulate neuroligin clustering at the synapse66. PSD-95 is also implicated in clustering of specific neurotransmitter receptors and signalling proteins to excitatory synapses62,67. Recent studies revealed that PSD-95 has dual effects on synapse specificity: it enhances maturation of excitatory synapses, but reduces the number of inhibitory synaptic contacts. These effects correlated with enrichment of neuroligin 1 at excitatory synapses and loss of neuroligin 2 from inhibitory contacts (for details see Chapter 7). In general, these investigations indicate that PSD-95 modulates the E/I synaptic ratio by enhancing clustering of neuroligins at excitatory contacts at the expense of inhibitory synapses.

Table 1. List of Genes Coding for Neuroligins and Postsynaptic Density Proteins with Their Chromosomal Position and Relevant Positional Information in Relation to Genetic Studies in Autism.

Name of the Protein, Official Symbol of the Gene

Location Positional Information in Relation to References Autism and Priority in Screening Genes

Neuroligin 1, NLG1

Neuroligin 2, NLG2

3q26-32 1. Linkage with autism was replicated at least once in a mega pedigree from (72-75) Finland. Lod score is > 4.18 2. Strongest experimental evidence of involvement in synapse maturation and differentiation 17p13.2 1. Reports of chromosomal rearrangements in this region leading to (20,76) autism phenotype

2. Report of linkage on chr 17p

3. 17p13.2 harbours a cluster of genes that represent good candidates for autism: NLGN2, DLG4 (coding for PSD-95), and GABA receptor-associated protein (GABARAP). GABARAP clusters GABA receptors by mediating interaction with the cytoskeleton

Neuroligin 3, NLG3 Xq13.1

Neuroligin 4, NLG4 Xp22.33

Postsynaptic density protein 95, 17p13.1 DLG4 [discs, large homologue 4 (Drosophila)]

Postsynaptic density protein 93, 11 q21 DLG2 [discs, large homologue 2, chapsyn-110 (Drosophila)]

4. This cluster of genes may be submitted to a common developmental regulation

Mutation already reported in autism. Need of further exploration (40)

Mutation already reported in autism. Need of further exploration (40)

1. Reports of chromosomal rearrangements in this region leading to autism (76) phenotype

2. Report of linkage on chr 17p (20) 1. Linkage to this chromosomal region has been reported in autism (77)

Neuroligin 4 Y linked, Yq11.221 Expressed in foetal and adult brain (78)

Understanding And Treating Autism

Understanding And Treating Autism

Whenever a doctor informs the parents that their child is suffering with Autism, the first & foremost question that is thrown over him is - How did it happen? How did my child get this disease? Well, there is no definite answer to what are the exact causes of Autism.

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