One Gene to Regulate Them All (or, at least many of them)

I have recently written about the complexities of the underlying genetics of autism, including issues of gene regulation. That particular article focused on RNA regulation through methylation. Now there is more evidence for the importance of RNA regulation in Nature. The CPEB-4 protein is involved in the addition of the poly-A tail to mRNAs, and there is a version that specifically regulates this in genes connected to autism.

Each mRNA–which allows the genes for proteins to be turned into those proteins–has a tail of adenosines (one of the nucleotides) added to it after it is transcribed from the DNA. This is important because when the mRNA is translated into a protein, a nucleotide is removed from the end of the RNA. The longer the tail, the more proteins can be made. If only short tails can be produced, there will not be enough proteins produced. CPEB-4 seems to be involved in regulating the length of the poly-A tail.

As already mentioned, things in the cell are complex. In learning more about this gene, I have learned that the protein, cytoplasmic polyadenylation element binding protein, is found in the dendrites and cell body of neurons, but that “treatment of neurons with ionotropic glutamate receptor agonists causes CPEB4 to accumulate in the nucleus. ” Here we again see a gene/protein related to autism connected to glutamate. Stress conditions in the brain–low oxygen or glucose, for example–cause CPEB4 to be sent from the cytoplasm to the nucleus, where they cannot do their job of regulating poly-A in the cytoplasm.

As noted, the CPEB4 gene seems to be central, but that doesn’t mean we should necessarily see mutations in it connected to autism. There could be mutations in the gene(s) for the ionotropic glutamate receptor, or in the gene(s) for glutamate production, or in some other regulator of CPEB4. So while you are bound to find popular articles out there crowing about the fact that there is a “central gene” connected to autism, don’t be mistaken: it’s still a complex situation.

Oxytocin and Autism II

Oxytocin is an important neurotransmitter, and one which has been implicated in autistic behaviors. Known as the “love hormone,” there’s a lot more to it than that. According to Psychology Today,

It regulates social interaction and sexual reproduction, playing a┬árole in behaviors from maternal-infant bonding and milk release to empathy, generosity, and orgasm. When we hug or kiss a loved one, oxytocin levels increase; hence, oxytocin is often called “the love hormone.” In fact, the hormone plays a huge role in all pair bonding. The hormone is greatly stimulated during sex, birth, and breastfeeding. Oxytocin is the hormone that underlies trust. It is also an antidote to depressive feelings.

As I have noted before, oxytocin has a dark side, meaning low levels of oxytocin not only reduce one’s desires for social interaction, but also reduces the tendency to engage in “groupthink,” the worst versions of which are racism and sexism. To the extent that autistics don’t engage in in-group/out-group thinking, we have a general tendency to not engage in racism and sexism.

However, do note many of the behaviors noted above. I suspect that it’s not just any empathy that’s affected by lower levels of oxytocin, but the specific kind autistics have problems with. Coincidentally, the kind of empathy we autistics have problems with is the same empathy that actually makes people favor their in-groups over out-groups and thus can make people behave in racist and less moral ways.

Also note that oxytocin is as much the sex molecule as the love molecule. I have read that many autistics have little to no interest in sex. While that’s certainly not universal (I’m sure other hormones, etc. are involved and affect sex drive as well), it seems to be much more common among autistics than neurotypicals. Low levels of oxytocin would explain this phenomenon. Ironically, since having sex increases oxytocin levels, those who lack interest in sex due to low oxytocin levels are behaving in such a way as to maintain low oxytocin levels.

The connection to trust is a bit odd to me, as I find autistics to be generally quite trusting. However, it may make sense if trust is tied to in-group members, and distrust to out-group members. Without that distinction, it may be that we are simply more trusting of out-group members, and thus we seem more trusting overall.

Here is an interesting overview of the research to day on the connection between oxytocin and autism. I have also written about the connection between touch and increasing oxytocin levels in a post titled Hugs Help.

A Variety of Genetic Pathways to Intense World Autism

Recent research into the gender bias of autism (4:1 in favor of males), has shown there are sets of genes that are expressed more by males than females which express certain sets of autism genes. In this research it was found that

Many of the shared genes in these sets are related to microglia, immune cells in the brain that trim away excess neuronal connections, or synapses, in the developing brain and that may be dysfunctional in people with autism. One of the sets also contains genes related to star-shaped cells called astrocytes, which may be involved in learning and memory; these cells are thought to be both smaller and denser in autism brains than in controls.

Failure to trim away extra neurons is a recurring theme when it comes to autism.

If microglia cannot work properly, we would expect less synaptic trimming to take place. Which means a hyper-connected/hyper-active network.

Astrocytes are involved in clearing away neurotransmitters, and if they cannot work properly, we would expect buildup of certain neuotransmitters. Surely some of those neurotransmitters would be glutamate, which acts as a positive feedback neurotransmitter. Which means a hyper-active network.

Genes involved in the glutamate-glutamine-GABA cycle would contribute to imbalances in these neurotransmitters. Imbalances in favor of glutamate would result in a hyper-active network.

Genes involved in serotonin production can affect synaptic trimming, since serotonin is needed to trim synapses. Low serotonin would result in less trimming, meaning a hyper-connected/hyper-active network.

Vitamin D is involved in serotonin production, and vitamin D deficiency has been connected to autism:

vitamin D hormone activates the gene that makes the enzyme tryptophan hydroxylase 2 (TPH2), that converts the essential amino acid tryptophan, to serotonin in the brain. This suggests that adequate levels of vitamin D may be required to produce serotonin in the brain where it shapes the structure and wiring of the brain, acts as a neurotransmitter, and affects social behavior. They also found evidence that the gene that makes the enzyme tryptophan hydroxylase 1 (TPH1) is inhibited by vitamin D hormone, which subsequently halts the production of serotonin in the gut and other tissues, where when found in excess it promotes inflammation.

As noted before, vitamin D absorption is affected by glutamine/glutamate levels.

In other words, mutations affecting microglia, macroglia, glutamate-glutamine-GABA production, serotonin production, and vitamin D levels can all have pretty much the same effect in having hyper-connected/hyper-active neurons. Those are a large number of causes resulting in essentially the same effect.

Shank Genes and Various Autisms

MIT reports they have discovered the role of a gene linked to autism. The Shank gene is involved in the maturation of synapses, and mutations in one of the Shank genes (there are three in humans) accounts for 0.5% of all known cases of autism–the largest known genetic cause. In their research, they have also found that Shank proteins are involved with another protein whose gene has also been linked to autism.

There are no doubt a large number of ways the brain can wire itself, from synapses not forming correctly to more synapses than usual (which can interfere with each other and thus result in the synapses not forming correctly), more or fewer dendritic spines, etc.

I am willing to bet that we will find a variety of autisms caused by certain families of relations. The autism caused by mutations that affect the Shank-Wnt interactions are likely to be quite different from those caused by imbalances in neurotransmitters that likely cause intense world autism. In each case, a variety of mutations can lead us down the same pathways. In the Shank-Wnt interactions, we can have mutations in any of the Shank genes or in the Wnt gene and get the same outcome. In intense world autism, mutations that cause overproduction of glutamate, the underproduction of glutamine, affect the production of serotonin, or affect the binding of vitamin D so the body can use serotonin, or affect the production or absorption of vitamin D can all create the same or similar conditions. Various causes can result in the same effect.

On this blog I mostly focus on what appear to be the causes of my and my son’s autism, but of course any of the causes of any of the autisms are worth looking into and understanding. But of course I say that as an information junky–which is practically the same thing as saying, as someone with autism.

GABA Receptor and Synaptic Pruning

Recent research suggests a role for GABA receptor in synaptic pruning. Autism (and schizophrenia) are often associated with a lack of synaptic pruning, meaning neurons are more active, with positive feedback dominating.

GABA is associated with negative feedback, meaning the brain slows down to a steady-state. Glutamine is similarly associated with negative feedback. Glutamate is associated with positive feedback. All of these are neurotransmitters. More, they are closely related to each other, and can be biochemically derived from each other.

This suggests a few potential pathways to autism. If there is a problem with the GABA receptor, you would not get enough pruning. But if there is not enough GABA being produced, you would have the same effect. A mutation on either the GABA receptor protein or on one of the enzymes associated with GABA production could have pretty much the same result.

Neurons with unpruned dendritic spines get more input than do those properly pruned. The more input a neuron (or other complex system) has, the more is acts as though there is positive feedback. Indeed, it can result in increasing cycles, driving more input. In essence the brain becomes more hyperactive, at least until a physical limit is reached, at which point the system crashes, cycling down.

The result is a more active brain that may have some difficulty learning new things, but which may at the same time show exceptional abilities because of the higher activity. While the senses themselves won’t show increased activity at the source, you would see increased activity in the brain, resulting in the sensory overload associated with autism. One would even expect a certain degree of “phantom” sensory information–as we see with schizophrenia. Indeed, this association between autism and schizophrenia (which I keep coming across in different ways) does suggest that the old categorization of autism with schizophrenia meant that the researchers at the time were on to something.

Also, unpruned dendritic spines is a feature of a child’s brain before they turn two (more or less). The fewer pruned dendritic spines (and less cell death of neurons, which also occurs around the age of two, in conjunction with the pruned dendritic spines) there is, the more an autistic person will act like they are two years old, perhaps even younger. This can explain the neotenous features of autism, even among those of us who are considered to be only moderately autistic. And if the brain is kept in a pre-verbal state by being kept in an even younger state than that of a two-year-old, it can go a long way to helping us understand why there are nonverbal autistics.

GABA and Unwanted Thoughts

New research shows that the neurotransmitter GABA, which has been connected to autism, is involved in the production of unwanted thoughts. Specifically, hippocampal GABA (would anyone be surprised to learn the hippocampus is also involved in autism?).

“Our ability to control our thoughts is fundamental to our wellbeing,” explains Professor Michael Anderson from the Medical Research Council Cognition and Brain Sciences Unit at the University of Cambridge. “When this capacity breaks down, it causes some of the most debilitating symptoms of psychiatric diseases: intrusive memories, images, hallucinations, ruminations, and pathological and persistent worries. These are all key symptoms of mental illnesses such as PTSD, schizophrenia, depression, and anxiety.”

I have always had a hard time suppressing thoughts, and I have been known to go over and over and over and over and over situations, replaying them and thinking of everything I could have and should have said. You may note other typically autistic symptoms in Dr. Anderson’s list, most notably anxiety.

The inability to control one’s thoughts is likely related to the weak executive functioning we on the spectrum have as well. After all, weak executive functioning makes it hard to not only control one’s thoughts, but to control expressing those same thoughts. While they may be two different systems, would it be surprising if it were found they were connected?