Decoding autism

About a year ago, I posted an article entitled Autism, which was meant to be more of an introduction into autistic spectrum disorders. Since then, I’ve been meaning to come back to this topic and provide more details about the mechanisms leading to autism, but I knew I need to do some proper research, which my student schedule didn’t really allow at that point.

The reason why I didn’t post any articles in the past three months is mainly my uni dissertation, which took up a lot of time. My chosen topic was Cellular mechanisms of autistic spectrum disorders. This assignment offered me the chance to read a lot of scientific papers and have a far better understanding of autism than I had before. As you probably guessed, this article draws quite a lot on my dissertation.

Some clarifications

When we refer to autism, we must be well aware that this is just an extreme end of the spectrum and that different neurodevelopmental disorders, sharing particular symptoms, are grouped under the term autistic spectrum disorders (ASD). The symptoms that characterise ASD are: impairments in social interaction, communication deficits and repetitive behaviours. Several factors have been linked to ASD, including gene dysregulations, alterations of the immune system and even environmental risk factors.

Discussing all the possible causes of ASD, could probably fit in a book, rather than a blog article, so I will only focus on gene dysregulations. However, if you have any kind of questions, feel free to post them in the comment section and I will try my best to answer them.

About glutamate and one its receptors

In biochemistry there are 20 different amino acids (the building blocks of proteins) and one of them is glutamate. This particular amino acid is very important because, apart from its role in the formation of proteins, it is also the main excitatory neurotransmitter in the brain. This means that glutamate is used to help the neurons communicate with each other and give rise to all sorts of brain activities we know about, including learning and memory.

When two neurons interact at the synapse (the space between the terminals of two interacting neurons), the neurotransmitter is released from the first neuron’s terminal and comes in contact with the second neuron’s terminal. But here’s the trick: in order for the neurotransmitter to have an effect on the second neuron, it has to activate certain structures on its terminal, called receptors. In the case of glutamate, there are three types of receptors, involved in different functions and with different mechanisms. The one we will be focusing on is the type I metabotropic glutamate receptor (mGluR). When this receptor interacts with glutamate, it leads to the translation of specific proteins involved in a process known as long-term depression (LTD), which influences learning and memory. Increased LTD is thought to play a key role in the development of ASD.

The FMRP protein

A few genes have been found to regulate the activity of mGluR and, through it, several cognitive processes. The Fragile X Mental Retardation 1 (FMR1) gene, which codes for the FMRP protein, is one of these genes. It interacts with mGluR-dependent proteins and is thought to regulate synaptic plasticity. During embryonic development, FMRP plays an important role in neural differentiation. Therefore, a mutation in the FMR1 gene leading to the absence of FMRP (a loss-of-function mutation) results in restricted brain development, impaired cognitive functions and autistic symptoms (previously mentioned). This mutation has been found in patients suffering from autism and especially from another brain disease, Fragile X Sydrome, which is the most common monogenic (determined by a mutation in a single gene) cause of autism. The activity of FMRP suppresses mGluR-dependent LTD, by inhibiting the synthesis of proteins involved in this process. Therefore, the absence of FMRP results in LTD, which primarily leads to mental disability.

Neuroligins and Neurexins

These represent transgenic protein families, which mediate synapse maturation in neurons using glutamate. Mutations affecting members of neuroligin and neurexin families have been found to be associated with autistic-like behaviours. The effects of these mutations on the brain are very specific, affecting cells in brain regions involved in learning and memory (CA1 pyramidal cells of the hippocampus, the Purkinje cells of the cerebellum), language (brainstem) and social interaction (somatosensory cortex). In normal situations, neuroligins and neurexins trigger mGluR-induced LTD, but their translation is inhibited by FMRP. The absence of FMRP leads to the loss of this inhibition, which results in mGluR-induced LTD.

Possible therapeutic strategies

Research on the links between mGluR transmission and genes involved in neural development resulted in a variety of therapeutic strategies for ASD. Genetic mGluR reduction and mGluR antagonists (drugs that act on this receptor by preventing glutamate to activate it) are the most common examples of treatments. Potential therapeutic candidates are Fenobam and Lithium, which act as antagonists at mGluR. Administered on animal models and on humans suffering from Fragile X Syndrome, these drugs have resulted in cognitive and behavioural improvements. Although there is hope in treating ASD, there is still a lot of research that needs to be done, especially since even diagnosing different autistic spectrum disorders is still a challenging task.

I hope this article gave you a little more insight into the mechanisms underlying autism and that you enjoyed reading it. As I mentioned above, any questions about this topic are welcomed.


Baudouin, S. J. (2014). Heterogeneity and convergence: the synaptic pathophysiology of autism. European Journal of Neuroscience, 39(7), 1107-1113.

Berry-Kravis, E., Hessl, D., Coffey, S., Hervey, C., Schneider, A., Yuhas, J., Hutchison, J., Snape, M., Tranfaglia, M., Nguyen, D. V. & Hagerman, R. (2009). A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. Journal of Medical Genetics, 46(4), 266-271.

Espinosa, F., Xuan, Z., Liu, S. & Powell, C. M. (2015). Neuroligin 1 modulates striatal glutamatergic neurotransmission in a pathway and NMDAR subunit-specific manner. Frontiers in synaptic neuroscience, 7, 11-11.

Etherton, M., Foeldy, C., Sharma, M., Tabuchi, K., Liu, X., Shamloo, M., Malenka, R. C. & Suedhof, T. C. (2011). Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proceedings of the National Academy of Sciences of the United States of America, 108(33), 13764-13769.

Gao, R. & Penzes, P. (2015). Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders. Current Molecular Medicine, 15(2), 146-167.

Nosyreva, E. D. & Huber, K. M. (2006). Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. Journal of Neurophysiology, 95(5), 3291-3295.

Rojas, D. C. (2014). The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. Journal of Neural Transmission, 121(8), 891-905.

Zalfa, F. & Bagni, C. (2004). Molecular insights into mental retardation: Multiple functions for the Fragile X mental retardation protein? Current Issues in Molecular Biology, 6, 73-88.

Image by Isuru Priyaranga