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A Time Window for Treating Autism?

One of the more popular theories explaining autism symptomology concerns an excitatory:inhibitory (E:I) imbalance in the brain [1, 2]. This states that an E:I imbalance leads to overexcitation in pyramidal neurons and thus the symptoms of autism. While E:I imbalance is potentially targetable via a number of interventions, such as GABA agonists, etc., the question remains: Is there a limited developmental window in which symptoms can be successfully reduced? With the paradigm in autism that “younger is usually better” that’s an important question to answer.

A new study suggests that, at least for certain causes of autism, treatment and rescue in adulthood is indeed possible. Using a mouse model to mimic CNTNAP2 mutations found in human cases, researchers at Stanford University have shown that not only do these mice exhibit behavioral and neurophysiological deficits akin to autism, if you use targeted treatment with optogenetics on the medial prefrontal cortex (mPFC) to specifically increase activity of inhibitory neurons and decrease that of excitatory neurons in that region, autism-like symptoms dramatically reduce.

While: 1) humans are not mice, 2) most people with autism don’t have CNTNAP2 mutations, and 3) using optogenetics is not a particularly viable treatment on humans– the series of experiments nevertheless show that it is theoretically possible to reduce autism symptoms even in a model that has structural brain malformations, which many scientists tend to assume are irreparable. It also lends support to the idea that the characteristic symptoms of autism in some cases may be functional in origin and therefore are potentially treatable, e.g., they are not the result of epileptic damage, etc. The problem then becomes identifying an individual’s specific physiological deficits and tailoring a treatment regime to him or her.

For instance, while Cntnap2 mutant mice in this study required treatments targeting both excitatory pyramidal neurons and inhibitory interneurons, another autism mouse model, Scn1a-deficient mice, can be easily rescued with typical GABA agonists, thereby targeting only interneurons directly.

To recap, this study is remarkable in a few ways:

  1. It shows that symptoms characteristic of autism can be rescued even in a brain that exhibits structural malformations.

  2. It reinforces the importance of the prefrontal cortex in autism, as targeting just the mPFC in these mice dramatically reduced symptoms in general. This is akin to my husband’s work using low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC).

  3. It suggests that although E:I imbalance may be an underlying cause in autism, its triggers can target different cell populations in different ways. While SCN1A mutations may largely impair the inhibitory cell population, CNTNAP2 mutations obviously impair both excitatory and inhibitory neurons, requiring treatments that target both those populations of cells. This realization may therefore lead to more refined approaches in personalized medicine.

  4. This study indicates that at least in some cases of autism, significant symptom reduction is theoretically possible well into adulthood, provided we are able to develop the means to target those cell populations successfully.

This last point will be the greatest challenge. But hopefully the move towards personalized and precision medicine will get us there.

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