KLE1738, GABA, and a Possible Autism Connection

I have written on the role of GABA in autism here and here and here. GABA is involved in calming neural activity, and having less of it is associated with autism. Now we have discovered a gut bacterium that seems to survive only on GABA.

Many of us on the spectrum also have gut problems. It may be that we need these bacteria, named KLE1738, but it also may be that one can have too many. Or, seemingly oddly, not enough.

It may very well be that one needs these bacteria to clear out GABA. Without enough KLE1738 to eat excess GABA, it’s likely that GABA would get converted back to glutamate (enzymes work both ways, after all). This would keep glutamate levels high, and glutamate both contributes to positive feedback in the brain and to leaky gut.

This may in fact  be the more likely scenario simply because too many KLE1738 would result in starvation and result in the numbers dwindling back to normal. At the same time, one could imagine a scenario where there is a boom-bust cycle of KLE1738, with an alternation between too many and too few. Both too many and two few would result in GABA imbalances. And these swings could also result in the seeming bipolar behaviors we see in many on the spectrum.

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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.

Autistic Bees

Yes, you read that title right. Researchers looking to prove the sociobiological theories of E. O. Wilson that social behaviors have a deep genetic source have found that socially unresponsive bees have genetic similarities to autistic human beings. Most notably, there were similarities in GABA receptors, voltage-gated ion channels, and heat-shock proteinsheat-shock proteins.

Variations in voltage-gated ion channels are going to affect the speed at which neurons work. This can result in hyperactivation (intense world) or hypoactivation, or even inactivation, if altered.

Heat-shock proteins specifically react to stressful conditions, and many are chaperone proteins (which help guide protein folding and, thus protein function). They are up-regulated during stressful conditions, and given their roles in gene regulation and protein stabilization, it’s not hard to imagine the kinds of detrimental effects changes in these proteins could cause.

The fact that similar differences in similar genes in bees and humans strongly suggests that animal social behavior is deeply conserved. And that means that autistic traits can also emerge in a variety of species when parallel mutations take place.

Executive Functioning, Creativity, and Autism

New research has shown that creativity mostly takes place in the cerebellum, while the executive functioning of the frontal lobe actually restricts creativity.

One of the features of autism (and ADD/ADHD) is impaired executive functioning. Among the things executive functioning does, according to Web MD:

  • Manage time
  • Pay attention
  • Switch focus
  • Plan and organize
  • Remember details
  • Avoid saying or doing the wrong thing
  • Do things based on your experience

When your executive functioning is impaired, you have difficulty with the above abilities. I recently wrote about the problems people with autism have with the last one on the list. The inability to make use of prior knowledge, then, is an executive functioning problem. While this seems to contradict my claims in the previous post, the place where concepts are formed — the hippocampus — is also a place where executive functioning takes place. And there are impairments with the hippocampus in those with autism — in particular, there are issues with oxytocin, about which I have written before. And as we have seen before, GABA is also involved. Those “unwanted” thoughts are the source of creativity.

All of this points to a brain that is structurally and biochemically different from more typical brains. And the connection between executive functioning and creativity also explains why autistic people tend to be very creative.

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?

GABA

I recently posted on the interconnections among glutamine, glutamate, and GABA. The only thing I noted about GABA is its role in reducing anxiety. However, there is research that shows that GABA is directly involved in the workings of the inhibitory neurons known as basket cells.

So glutamate, which is involved in the excitatory neurons, is transformed into GABA, which is involved in inhibitory neurons. For those whose autism is caused by IWT, it seems that it would be worth looking at the glutamate-GABA pathway.

Tummy Trouble–Autism and the Gut

I read an article once that said Celiac disease is in part caused by having a leaky gut. Because I have an allergic reaction to gluten, but not full-blown Celiac disease (perhaps), I decided to look up what causes leaky gut and how to take care of the problem.

The problem: the pores are too wide.

The solution: probiotics and glutamine.

Glutamine is an amino acid related to the amino acid glutamate. For you chemistry types, the difference between the two is on the R-group. The OH on the glutamate is replaced by an amine — NH2. Glutamate is made from glutamine, and vice versa. However, it is possible for there to be a mutation on a gene that would result in an enzyme that prefers one over the other.

In some people with autism, there is very high glutamate in the brain. In fact, glutamate is an excitatory neurotransmitter, which implicates it in IWT autism. As it turns out, such autistics not only have high glutamate, but low glutamine as well. If the body is preferentially making glutamate over glutamine, this could not only cause autistic behaviors, but leaky gut and potentially gluten allergy as well. And perhaps not just gluten allergy, since leaky gut can result in a variety of food allergies.

This glutamate-glutamine connection to autism explains why so many on the spectrum have gut problems.

The above linked article also notes that “levels of GAD 65 kDa and GAD 67 kDa proteins, both of which are involved in converting glutamate to GABA, are reduced in the brains of individuals with autism, resulting in increased levels of glutamate in the brain substrate.” Why is this important? Low GABA levels increase feelings of anxiety. Social anxiety is, of course, a main feature of autism.

Thus, a system that preferentially makes glutamate over both GABA and glutamine would, it seems, result in someone having autism. Also, it seems that eating things that could provide GABA and glutamine might reduce some of the negative behaviors associated with autism. Indeed, there does seem to be some research which suggests glutamine supplements could help.

In fact, my son and I now take glutamine if 1) our stomachs are upset and/or 2) if we anticipate eating wheat. And it works. Without it, my son will throw up when he eats wheat, but with it, he won’t even complain about his stomach hurting. Now, in case you’re wondering if there’s a placebo effect, once my son was complaining about his stomach being upset. I couldn’t find any glutamine, but found something else and told him it was glutamine. He threw up anyway. Every other time he had complained about his stomach hurting and I gave him actual glutamine, he was fine.