Showing posts with label Autism. Show all posts
Showing posts with label Autism. Show all posts

Sunday, September 19, 2010

Neuroligin and Autism

ResearchBlogging.orgThe rapid increase in autism spectrum disorder (ASD) diagnoses over the last 15 years is alarming. A number of reasons for the rise have been suggested, some of which have sparked debate that occasionally becomes laden with vitriol. Many people, surprised and frightened by what they see as the unprecedented appearance of a novel disorder, are looking for answers and pointing fingers at parties they feel may be culpable. The etiology of ASD is unknown, and perhaps we will find that some of the impassioned claims made by groups like Generation Rescue are valid. But the idea that the emergence of such a disorder occurred overnight is not completely accurate.

Perhaps the earliest documented case of autism was that of Hugh Blair in 1747 (he was 39 at the time). Over the years other cases were identified, while many were misdiagnosed (frequently as infantile schizophrenia). In the 1940s, Leo Kanner and Hans Asperger developed the foundation for the modern diagnosis of autism by laying out a clearer description of the disorder. Interestingly, Kanner was disturbed by how quickly the rate of diagnosis of new cases of autism rose after his paper was published. This was in the 1950s. Since then, of course, the diagnosis has been refined and subsequently broadened, resulting in the class of ASDs we are familiar with today. In many ways, the history of autism up to this point is not so different from the history of other debilitating disorders like schizophrenia in that it consists of slow acknowledgement of a unique set of symptoms, followed by attempts at classification and an increase in the number of diagnoses due to clearer diagnostic criteria.

How the story of autism plays out is yet to be seen. But as the debate over vaccines and other potential causes continues to smolder, science is plodding along attempting to develop animal models for the study of the disorder. Several genetic mutations have been associated with ASDs. Mutations in genes that encode for proteins involved in the healthy functioning of synapses, called neuroligins and neurexins, have been directly linked to ASD. The result has been that many now classify the disorder as a synaptopathy, or a disease that is primarily caused by synaptic dysfunction. This has also led to the development of neuroligin-3 knockout (KO) mice as a rodent model for ASD.

A study in this month’s issue of The Journal of Biological Chemistry goes a step further in determining exactly how mutations in neuroligin can result in synaptopathies. The group coerced cultured neurons to express neuroligin mutations, which caused the protein to be folded improperly after it was manufactured. Furthermore, the misfolded proteins were not sent from the cell body out to the limits of the neuron. Thus the dendrites had a dearth of the protein, a factor that could be at least partly responsible for the unhealthy synaptic function that occurs when the neuroligin gene is mutated.

Protein misfolding is a culprit in Alzheimer's and Parkinson's disease as well, among others. While this study is an important step toward understanding autism, there are many more questions to be answered about how dependent the disorder may be upon protein misfolding and what other factors may be contributing to its variety of symptoms. And unfortunately attempts at developing treatments for protein misfolding diseases have not yet met with much success. Regardless, this is a positive development in understanding ASDs, a task that remains important not just for their treatment but for quelling the anxiety of a public struggling to understand the troubling incidence of the disorder.

De Jaco, A., Lin, M., Dubi, N., Comoletti, D., Miller, M., Camp, S., Ellisman, M., Butko, M., Tsien, R., & Taylor, P. (2010). Neuroligin Trafficking Deficiencies Arising from Mutations in the / -Hydrolase Fold Protein Family Journal of Biological Chemistry, 285 (37), 28674-28682 DOI: 10.1074/jbc.M110.139519

Thursday, June 26, 2008

It's All About Timing: Circadian Rhythms and Behavior
Anyone who has ever tried to drastically alter his or her sleep schedule (e.g. going from working days to working nights) knows that it is one of the more difficult biological tasks we can take on. Even altering one’s sleep patterns by a couple of hours (such as the shift experienced by cross-country travelers) can be disruptive, and enough to make us feel tired, mentally unclear, and grumpy. But why are we so inflexible when it comes to our daily routine? Why are our otherwise diverse bodies so sensitive to an adjustment of our biological clocks by just a few hours? Perhaps it is because millions of years of evolution have led to a daily body clock so fine-tuned that this sensitivity is adaptive.

Circadian (from the Latin for “around” and “day”) rhythms are endogenous biological patterns that revolve around a daily cycle. They are found in all organisms that have a lifespan that lasts more than a day. They are adaptive in the sense that they allow an organism to anticipate changes in their environment based on the time of day, instead of just being a passive victim to them. Thus, to foster that readiness, they usually involve the coordination of a number of physiological activities, such as eating/drinking behavior, hormonal secretion, locomotor activity, and temperature regulation.

A major nucleus of the mammalian brain, located in the hypothalamus and called the suprachiasmatic nucleus (SCN), is responsible for acting as the master time-keeper in mammals. When the SCN is lesioned (i.e. in rodents), it results in a complete disruption of circadian rhythms. The animals will demonstrate no adherence to a daily schedule, sleeping and waking randomly (although still sleeping the same total amount of time each day).

The SCN receives information from ganglion cells in the retina, which keep it appraised of whether it is light or dark out, and maintain its synchrony with a diurnal schedule. It is not, however, completely dependent on visual input for keeping time. A number of other environmental cues, such as food availability, social interaction, and information about the physical environment (other than light) are thought to play an important role in the SCN’s ability to maintain regular daily rhythms.

Although the SCN is the center for circadian rhythms, it seems that many individual cells are not directly controlled by the SCN. Instead, they are thought to maintain their own time-keeping mechanisms. Known as peripheral oscillators, these cells are present in a number of organs throughout the body, and can be sensitive to environmental cues as well as the signals of the SCN.

So, how do the neurons of the SCN actually “keep time”? They appear to be controlled by a cycle of gene expression, which consists of a natural negative feedback mechanism. Throughout the day, a gene known as CLOCK (circadian locomotor output cycles kaput) is activated based on daytime environmental cues. This gene acts with another, BMAL1, as a transcription factor, driving the transcription of proteins period (PER) and cryptochrome (CRY). When large amounts of PER and CRY have been created, they form a complex, and act on the CLOCK and BMAL1 genes to inhibit their own expression. This occurs during the night, and the result is that PER and CRY proteins become diminished, allowing CLOCK and BMAL1 to begin transcribing them again. This happens around the morning of the next day. Thus, the feedback loop is synchronized with a 24-hour cycle, allowing the clock in the SCN to oscillate at a regular rate.

Disorders of the SCN can result in disruptive sleep problems, such as advanced sleep phase syndrome (early sleep and wake times) or delayed sleep phase syndrome (preference for evenings and delayed falling asleep). More attention is now being focused on the role a dysfunctional circadian system may play in already identified behavioral problems. A recent review in PloS Genetics examines the potential influence circadian rhythm disturbances may have in disorders like depression, schizophrenia, and even autism.

Circadian disruptions are present in all major affective disorders, including depression, bipolar disorder, and schizophrenia. Although the exact role circadian rhythms play in these disorders is not yet known, it may be substantial. This is supported by the influence changes in sleep patterns can have on the alleviation of primary symptoms of these disorders. For example, sleep deprivation has been demonstrated to have an antidepressant effect (albeit short-lived) in patients. And some affective disorders, such as seasonal affective disorder, seem to have a basis in the length of the day, and shape emotional states.

Autism spectrum disorders (ASD) are correlated with low melatonin levels, and a gene responsible for the synthesis of melatonin is considered a susceptibility gene for autism. Mice with a mutant form of this gene demonstrate deficits in social interaction, anxiety, and increased occurrence of seizures. It is postulated that behavioral problems in ASD may be influenced by the failure of an individual’s circadian clock to effectively take note of social and environmental cues.

Variants of a number of time-keeping genes, such as PER1, CLOCK, and CRY have been found to be associated with behavioral disorders. It has yet to be determined if these variations are causative, contributive, or unrelated to the disorders. Keeping in mind how influential a disturbance of circadian rhythms can be in our daily lives, however, it seems logical to investigate the possibility of their contribution to pathologies.


Barnard, A.R., Nolan, P.M., Fisher, E.M. (2008). When Clocks Go Bad: Neurobehavioural Consequences of Disrupted Circadian Timing. PLoS Genetics, 4(5), e1000040. DOI: 10.1371/journal.pgen.1000040

Monday, February 11, 2008

Autism May Involve Limited Awareness of Self

As the prevalence of autism continues to rise—for reasons that are still unknown—researchers are frantically trying to understand the disorder. Autism consists of a spectrum of behaviors, such as repetitive or ritualistic behavior, self-injury, impaired language ability, and limited communication skills. One of the most commonly held views on autism has been that those who are afflicted have a decreased capacity to feel empathy, or to understand that other people have their own mental states, desires, and intentions. Neuroimaging studies with autistic individuals have seemed to support this idea.

Other studies have indicated there is a diminished ability to recognize self in the autistic mind as well. A neuroimaging study released this week supports that hypothesis. The experiment used fMRI and a relatively new technique called hyperscanning to measure brain activity of autistic and non-autistic adolescents as they played an interactive game together. Hyperscanning is an imaging method that allows multiple people to be scanned with fMRI simultaneously as they communicate with one another.

The researchers compared the fMRI images to images they had taken of athletes’ brains as they imagined themselves taking part in athletic activities. They found this focus on “self” caused high activity in the cingulate cortex, an area previously implicated in self-awareness and social interaction. This area was also highly activated in the non-autistic participants in the game as they thought about what action they would take. It contrasted with a different pattern of activity that occurred when they thought about the actions of their partner. Although the autistic participants were able to play the game effectively, they showed much lower levels of stimulation in the cingulate cortex. The activity was also negatively correlated with the severity of their autistic symptoms (the more severe the symptoms the lower the activity).

All of the autistic participants in the study were considered high functioning, with normal or high normal intelligence quotients. The research group plans to conduct more imaging experiments in the future with autistic individuals who have lower IQs. For now, this experiment may shed more light on the brain mechanisms underlying autism. It also adds more complexity to the problem, however, as it appears a deficit in the awareness of others may not be all that’s involved.