Autism is a blanket term for a set of specific mental and physical disabilities, which may stem from a variety of underlying genetic issues. One known cause of autism is termed 'Fragile X' syndrome (FXS), and affects 0.4-0.8 per 1000 males, and 0.2-0.6 per 1000 females; symptoms range from mild to severe.
Autism is a blanket term for a set of specific mental and physical disabilities, which may stem from a variety of underlying genetic issues. One known cause of autism is termed ‘Fragile X’ syndrome (FXS), and affects 0.4-0.8 per 1000 males, and 0.2-0.6 per 1000 females; symptoms range from mild to severe.
FXS is associated with a mutation of the ‘fragile X mental retardation 1’ (FMR1) gene on the X-chromosome, which explains the disparity in prevalence rate between males and females. The FMR1 gene controls the expression of a protein, FMRP, which is crucial for neural development (as well as having a significant role in healthy sexual maturation). The likelihood of the mutation existing is actually higher for females, but the second X-chromosome usually acts as a substitute for the affected gene to inhibit the penetrance (likelihood of a gene expressing an associated phenotype) of the mutated version, and symptoms are often mild or imperceptible. For males, the lack of a second X-chromosome means that when affected, penetrance will necessarily be close to 100%.
How the FMR1 gene is expressed
Expression of the mutated FMR1 gene manifests as a range of physical characteristics, including flat feet, elongated facial features, double-jointedness and protruding ears. The psychosocial effects include low IQ (averaging 40 for males with the gene fully ‘off’), social anxiety, ADHD, hyperactivity, reproductive abnormalities, and various behaviors and movements such as arm-flapping and repetitive speech. FXS sufferers are often beset by various health complications including sinusitis, lazy eye, ear infections and even seizures. Females with one healthy X-chromosome mediating the effect of the mutated copy usually exhibit much milder symptoms, including slightly below-average IQ and minor developmental problems. There are currently no approved drug treatments for FXS, and the condition is usually managed using therapy and behavioral programs. However, researchers at the University of California, Irvine discovered that a endocannabinoid, 2-arachidonoylglycerol (2-AG), was capable of significantly improving behavior, responsiveness and level of anxiety when used to treat mice already genetically altered to express FXS symptoms. It is important to note that the level of molecular precision required for carrying out these incredibly complex and delicate processes could never be achieved by simply consuming cannabis. Phytocannabinoids are not specifically tailored to the requirements of the eukaryotic endocannabinoid system, despite prevalent misconceptions surrounding the differences between phytocannabinoids – found in plants – and endocannabinoids, naturally produced in the bodies of humans and animals. Endocannabinoids, (and increasingly, their synthetic counterparts) are far more specialized for their unique physiological functions, and have fewer side-effects within the body. Through a highly complex process, FXS inhibits the neural dendrites, the tree-like structures – each ‘twig’ (properly termed ‘spine’) ending in one synapse – that control the movement of information-bearing neurotransmitters. The inhibition causes a knock-on effect in the hippocampus, responsible for spatial navigation and memory, and the cerebellum, which controls movement, cognition and regulation of fear and pleasure responses. In wild-type mice this disorder usually manifests as heightened anxiety and motor activity, as well as increased tolerance of open spaces (not a survival trait for mice). Researchers hypothesized that introducing increased levels of the endocannabinoid 2-AG into affected brain tissue would, over time, mediate the effect of the missing protein. They were astonished to find significant improvements in the affected mice within just a few hours.
2-AG in the neural dendrites
In the hippocampus, the vital protien FMRP is mainly found in the dendrites protruding from the body of the neural cell. The membranes on either side of a synaptic junction, where cells in close proximity ‘communicate’, are covered in neurotransmitter receptor proteins, more commonly known as receptors. These enable the movement of information via neurotransmitters. The faulty FMR1 gene switches off the production of FMRP, which is responsible for neural signaling and transportation of messenger RNA (mRNA), as well as for the synthesis of various essential proteins. The resulting lack of FMRP seriously compromises healthy synaptic function.
2-AG and the mGluR-5 receptor
One receptor that is affected by silencing the FMR1 gene is the metabotropic glutamate receptor-5 (mGluR-5), which is inhibited by the reduction in transmissible mRNA at the synaptic junction. On the other side of the junction, the CB1 receptor is also affected, as it receives a reduced load of 2-AG. The mGluR-5 receptor is first stimulated by glutamate, and this stimulation results in an increase in another protein (known as DGLa). The increase in DGLa in turn increases the level of 2-AG in the synapse.
In the above diagram, the mGluR-5 receptor works as normal for both examples, channeling glutamate to the FMRP. On the left, the absence of FMRP prevents the flow of polyribosomes (proteins that transport mRNA) to DGLa molecules on the membrane, which in turn are unable to produce the required levels of 2-AG needed for CB1 receptor activation. For 2-AG to remain stable and able to perform its crucial metabolic functions, its degradation rate (the rate at which it reacts with other proteins to form new chemicals) must be low to non-existent. Previous research has shown that 2-AG is primarily (~85%) degraded by the monoacylglycerol lipase (MAGL) protein, an enzyme that is controlled by the MGLL gene. Therefore, inhibiting the MGLL gene reduces the level of MAGL protien present in the dendrite, and thus reduces the degradation rate of 2-AG. In 2009, it was discovered that another protein (JZL184) directly inhibits the MGLL gene, drastically reducing expression of MAGL and causing 2-AG levels in test mice to rise in response. Mice treated with JZL184 showed heightened expression of 2-AG within just six hours, and performed better in maze tests that included evaluating anxiety and tolerance of open spaces. Such results, although encouraging, will require further investigation prior to the development and marketing of a drug treatment for autistic humans. It is likely that such research will be undertaken soon, given the relatively high prevalence rate of FXS and the current lack of a cure. However, it is not anticipated that the development of human-specific therapy will lead to an outright cure, but rather that ameliorative treatments will be yielded, enabling FXS sufferers to socialize normally and achieve a greater degree of independence in everyday life.