Exploring the neural basis of autism: insights from single gene disorders

Autism spectrum disorders (ASD) have a complex genetic basis and  despite much research the identities of the defective genes remain elusive. However, there are several disorders that are caused by a defect in a single gene, causing a!ected individuals to display autistic traits. Rett’s syndrome and fragile X syndrome are two such disorders with high prevalence of autism that are caused by mutations in single genes, both located on the X chromosome. Why are these disorders important in gaining insight into the autistic brain? One view is that by examining the role of the proteins encoded for we may "nd a way to correct what has gone wrong in the intricacies of brain wiring.

Autism spectrum disorders (ASD) have a complex genetic basis and despite much research the identities of the defective genes remain elusive.  However, there are several disorders that are caused by a defect in a single gene, causing affected individuals to display autistic traits. Rett’s syndrome and fragile X syndrome are two such disorders with high prevalence of autism that are caused by mutations in single genes, both located on the X chromosome. Why are these disorders important in gaining insight into the autistic brain? One view is that by examining the role of the proteins encoded for we may find a way to correct what has gone wrong in the intricacies of brain wiring.

The human brain is comprised of neurons - about 100 billion of them - that communicate with each other via specialised cell-to-cell junctions known as synapses. There are excitatory synapses that facilitate information flow and inhibitory ones that dampen the likelihood of one neuron firing another. While the basic connectivity of our brain is set up before birth by a host of genetic programmes, these predetermined connections are validated and refined throughout our lifespan on the basis of our experiences. Your brain has more synapses as a toddler than as an adult, hence a remarkable capacity to undergo changes during these early years. For example, while you struggle to master a new language as an adult, you do not even recall how you learnt to speak as a child. During your early development there is selective ‘weeding out’ of this excessive number of synapses depending on specific experiences. From what we know so far, activity at excitatory synapses are thought to determine what connections a particular neuron maintains or eliminates with its surrounding neighbours. 

The establishment of normal synaptic connectivity is a precise, developmentally orchestrated process. However, it is still poorly understood how these synaptic connections produce cognition, emotions and physiological responses. Errors in synaptic connectivity are thought to be associated with neurodevelopmental disorders such as ASD. For example, a fundamental skill an autistic child struggles with is learning to speak. To most of us this is automatic, but perhaps incorrect wiring of synapses could account for traits like this. Do single gene disorders provide any evidence for such a claim? And if so, is there a way to correct the inherent mistake?

At the University of Edinburgh, Prof. Adrian Bird’s lab explores the molecular basis of Rett’s syndrome, which almost exclusively affects females with a prevalence of 1 in 10,000-15,000 female births. Males with the same mutation die by two years of age as they lack a normal copy of the mutated gene. Rett’s is particularly devastating because a period of normal development is followed by dramatic loss of acquired skills. Symptoms occur between 6-18 months of age and include loss of motor skills, breathing problems, and loss of purposeful hand movements, which are replaced by stereotypic repetitive hand movements - a shared trait with autism. The condition then stabilises with most patients surviving into adulthood.

Most cases of Rett’s syndrome are caused by mutations in a gene called MECP2 (methyl CpG binding protein 2). It encodes for MeCP2, a protein abundant in the brain that is implicated in silencing gene expression. Mice lacking MeCP2 are used as a model of Rett’s syndrome and have aided our understanding of the disorder. Surprisingly, studies in the mouse brain show that in the absence of MeCP2, there are few large magnitude changes in gene expression despite the fact that these mice die prematurely at 6-8 weeks of age. This suggests that MeCP2 may regulate many genes moderately rather than silencing key genes. The numbers of synapses are shown to decrease with loss of MeCP2 and increase with gain of MeCP2 suggesting a role for MeCP2 in regulating synaptic connectivity. Therefore, abnormal synaptic connectivity due to loss of MeCP2 may explain some of the autism-like aspects of Rett’s.

Strikingly, mice missing MeCP2 can be rescued by the reintroduction of a correct copy of the gene, even those that have already developed Rett-like symptoms. This shows that the brain is not permanently altered despite the fact that Rett’s is often described as a neurodevelopmental disorder, which is hopeful for devising late stage therapeutic interventions. Despite such heartening developments, the precise function of MeCP2 is still unclear. Controversially, some have suggested that MeCP2 does not function to silence genes but acts to switch genes on instead. Recent work in the Bird lab suggests that MeCP2 does not act on specific genes in the brain but is important for how genes are organised and packaged throughout the chromosome, consistent with the dramatic consequences of mutating it.

Fragile X is a similar neurodevelopmental disorder and is also being studied in Edinburgh by Prof. Peter Kind’s lab. This disorder affects one in 3000-4000 males and one in 6000-8000 females. Many children with fragile X show intellectual disabilities with varying behavioural deficits. A developmental delay in motor skills and heightened sensory responses are thought to underlie most of their symptoms and about 70% of fragile X children display at least one autistic trait. For example, commonalities between fragile X and autism are found at a cognitive level in skills involving social interactions such as maintaining eye contact.

Prof. James Watson described the discovery of the gene mutated in fragile X, FMR1 (fragile X mental retardation 1), in 1991 as “The first major triumph of the Human Genome Project”. When mutated, the gene is silenced and consequently there is no production of the protein FMRP (fragile X mental retardation related protein), which is thought to regulate protein synthesis at neuronal synapses. In mouse models of fragile X there is dysregulated neuronal protein synthesis and disrupted synaptic connectivity: changes in structure of excitatory synapses as well as an imbalance in neuronal excitation and inhibition. So FMRP appears to be critical in fine-tuning the synaptic connections our brains make. The obvious question then is what are the FMRP regulated proteins and how does it work?

To date one of the most promising theories of the underlying fragile X causes posits that loss of the FMRP protein leads to exaggerated effects of a receptor found at our excitatory synapses. In the mouse model, reducing levels of this receptor alleviates several disease symptoms. In the wake of such encouraging results, phase one clinical trials are underway involving drugs that target this receptor.

While errors in the processes of synaptic connectivity may not solely explain the neural basis of autism, increasing evidence from studies of single gene disorders suggests this to be a similarity observed in their brains. Exploring the neural basis of the autistic brain is of fascination for neuroscientists for several reasons: understanding the diseased state goes hand in hand with deciphering how our brain works normally, it opens the door to a collaborative effort that could well erase the myths and misconceptions surrounding autism and the improvement of therapeutic strategies. The head of research programmes at the FRAXA foundation, Dr. Michael Tranfaglia, says this about his son Andy who has fragile X: “Our lives are changed forever by our children with developmental disorders and we are challenged on a daily basis by our own fragile X experience. Better understanding of the basic biology of fragile X has already given us novel treatments, which have improved my son’s life (and that of my whole family) dramatically.”