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, September 9, 2010

The Many Sides of GABA

If you have a superficial level of knowledge about neuroscience, you probably won’t associate psychostimulants with gamma-aminobutyric acid (more commonly known as GABA). Just as you learn in early biology that a mitochondrion is the “powerhouse of the cell”, you learn in early neuroscience that GABA is the “primary inhibitory neurotransmitter of the brain”. And while this is often true (exceptions are being found on a regular basis), it perhaps doesn’t do justice to the diversity of roles that GABA can play.

There are, for example, many instances of GABA having an inhibitory effect on another inhibitory neuron. This can in effect stop the inhibition, potentially allowing for excitation by another neurotransmitter. Exactly this happens every time you make a voluntary movement. Neurons in the striatum release GABA that inhibits the action of neurons in the globus pallidus. These neurons normally inhibit areas of the thalamus that are necessary for movement but when they are inhibited the thalamus is essentially freed up, allowing us to move.

So, GABA-ergic actions don't necessarily mean inhibition as an end result. This is also true when it comes to the addictive properties of drugs. Dopamine (DA) neurons in the nucleus accumbens (NAc) directly modulate GABAergic connections to the ventral pallidum (VP), which itself sends GABAergic projections back to the NAc. Thus, it is easy to imagine that influencing DA transmission in the NAc, an inevitable outcome of drug use, also has an effect on GABAergic activity throughout the reward system.

Because of this, researchers like Claire Dixon and colleagues have been interested in how GABAa receptors are affected by the administration of drugs like cocaine. In a study published earlier this year in PNAS, Dixon et al. used knockout (KO) mice that had the gene for the alpha2 subunit of the GABAa receptor deleted. GABAa receptors containing these subunits are highly expressed in the NAc.

While these KO mice still demonstrated a stimulant response to cocaine (based on locomotor assays), they failed to show sensitization to the drug, i.e. their activity remained the same on repeated administrations while the wild-type (WT) mice's activity progressively increased. Additionally, cocaine's ability to facilitate conditioned reinforcement (lever pressing) was vastly reduced in the KO mice.

This indicates that GABA may have a role in mediating an addictive response to drugs. The authors hypothesize that the ability of cocaine to increase behaviors associated with environmental cues connected to the drug (lever pressing), and with conditioned activity (sensitization), may depend upon GABAa receptors. Alpha-2 subunits may allow cocaine to strengthen the association between cues and a drug, an association that underlies some of the most compulsive aspects of addiction. Thus, perhaps GABA receptors represent a potential, if not unlikely, target for treating addiction.

Dixon et al. (2010). Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAa receptors. PNAS, 107, 2289-2294.