Scitech | Autism and the plastic brain

It’s all about communication and connectivity

According to the Centre for Disease Control and Prevention (CDC), an estimated one in 68 individuals in the United States are currently diagnosed with Autism Spectrum Disorder (ASD); a prevalence that has been rising since the 1970s. Although the increase in numbers is likely a primary result of broadened diagnostic parameters, these statistics have been turning heads in recent years and drawing the public’s attention. Accordingly, researchers have begun seriously considering a long-standing question: what is ASD and how does it occur? To be clear, vaccines, are not the correct answer to the latter.

ASD, colloquially known as Autism, is primarily characterized by difficulties with social interaction, lack of verbal and nonverbal communication, and repetitive or restrictive behavior, such as lining up and ordering objects. In addition to these core challenges, individuals may also present with altered learning and memory, epilepsy, aggression, sleep disorders, anxiety, and depression. Because it is a spectrum disorder, different individuals with ASD will experience these problems to a greater or lesser degree, which will differentially affect their lives. As a consequence, the journey to understand and treat ASD is complicated and has historically been misguided.

Up until the late 1960s, it was common belief that Autism was due to a lack of maternal affection toward their child and the derogatory term “refrigerator mothers” was coined as a description for the cause of the condition. This non-evidence-based label undoubtedly caused distress, and certainly did not provide suitable grounds for thorough biomedical investigation.

We now understand that the genetic makeup of an individual, in combination with certain high-risk genetic mutations, is paramount for ASD etiology and susceptibility. The problem is that ASD is largely polygenetic in nature, meaning it results from alterations of multiple genes involved in a variety of functions. This makes studying ASD particularly challenging and has necessitated the use of tedious investigative paradigms.

The current strategy for understanding ASD implements a ground up approach. Scientists start with the identification of genes involved in the development of ASD, particularly in patients with de novo mutations compared with unaffected family members. With this information, scientists can understand how certain molecules and proteins work in neuron to neuron communication, how these connections make functional circuits in the brain, and how these circuits function in one or multiple brain regions ultimately governing behavior.

We are starting to identify clusters of genes involved in common functions, thereby giving us clues into the cellular and molecular basis of ASD. The regulatory mechanisms of protein synthesis and neuroplasticity have become a major candidate in this regard.

mRNA translation is the process by which new cellular proteins are synthesized based on the genetic code of an organism. This is required for cell growth and function throughout the body, and maintains physiologic homeostasis. In the brain, protein synthesis is elaborately regulated to ensure appropriate communication between neurons and within neural circuits.

Connections that are too strong or too weak can lead to aberrant brain function. Neuroscientists are speculating that this imbalance between excitatory and inhibitory (E/I) neural activity is involved in ASD pathogenesis. Importantly, the Sonenberg lab at McGill University described how dysregulation of the translation machinery resulting in enhanced synaptic protein synthesis leads to an ASD-like phenotype in mice. Can we, then, therapeutically target regulatory mechanisms of translation, correct E/I imbalance, and reverse ASD pathophysiology? The answer is: maybe, but it’s not easy.

Because it is a spectrum disorder, different individuals with ASD will experience these problems to a greater or lesser degree

Current drug treatment options for ASD are scarce and offer little support for the core symptoms. Unfortunately, since Autism is a spectrum disorder with a wide range of genetic heterogeneity, researchers are unlikely to find a therapeutic for every genetic cause of ASD or to find one common treatment for every case.

Furthermore, the process of designing effective neurological medication is complicated by poor drug delivery into the central nervous system (i.e. penetration of the blood brain barrier), in addition to off-target effects when it does enter the brain. Since neural function is fundamentally interconnected, correcting one problem often causes new complications to arise. In general, these challenges have made the quest for discovering effective neurologic pharmaceuticals slow and frustrating.

The future of ASD research, however, is more promising. Similar to the current strategy of targeting the translation machinery in cancer, we may be able to use this approach in the case of ASD.

Since translation is regulated at many levels, there are likely druggable targets that, when their function is attenuated or enhanced, may correct core deficits in ASD. This would indeed, on a physiological level, necessitate profound rewiring of neural circuitry and reshaping of cell-to-cell connectivity. Is such a phenomenon even possible? Should we even pursue such an end?

It was once thought that connections between neurons are hardwired and unchanging but we now understand that they are flexible, plastic, and can change over time. Regulated protein synthesis is indispensable for appropriate neuroplasticity. This ability has considerable implications for how memory is stored in the brain, the way we learn to interact with our surrounding environment, and ultimately how we experience life. The issue is, then, how would chemically altering neural activity with therapeutics change that experience? Furthermore, can we correct behavioral defects without altering other aspects of one’s life, such as their personality or even their memories?

Even though our relatively plastic brains can be rewired, this does not necessarily mean that they should. ASD may be experienced as a real disorder to some, but for others this may not be the case.

Steve Silberman, in his book about Autism and Neurodiversity, states that “By autistic standards, the “normal” brain is easily distractible, is obsessively social, and suffers from a deficit of attention to detail and routine. Thus, people on the spectrum experience the neurotypical world as relentlessly unpredictable and chaotic, perpetually turned up too loud, and full of people who have little respect for personal space.” In part, the lack of understanding, on a personal level, makes integration into typical society difficult for some with ASD.

However, the lack of understanding, on a scientific level, makes it nearly impossible to find real and effective solutions. In seeking to understand ASD, we are not only taking steps forward to help those in need, but we are given the opportunity to see into a new world from a new perspective. If we can communicate, we can connect; if we can connect, we can understand; and if we can understand, we have a hopeful future. I am talking, of course, about the inner workings of Autism and the plastic brain.

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