depressed black lab (Photo credit: CC: Lecates 2007, Newtown, Alpharetta, GA, US)
(Photo credit: CC: Lecates 2007, Newtown, Alpharetta, GA, US)

We used to have a dog, Hubert Beagle-Basset, who suffered from a severe case of separation anxiety. Whenever we came back home, even if we had only been gone for a short period of time, he used to run joyous circles around the dining room table—we used to call them victory laps.

Our present dog Sherman, a big black lab, suffered from depression when we got him from the San Francisco SPCA shelter. He had already been there twice. We tried to let him know that he had hit the jackpot coming to live with us. But he was so insecure that he didn’t wag his tail for a whole year.

He’s fine now—he wags his tail a lot—but he is still pretty “weird.” If he isn’t out for a walk or eating, he is hiding out in our closet. He loves the small dark space and he loves being alone.

 

Canine psychiatry

I am pretty sure Sherman would qualify for the canine diagnosis of introverted personality. Ask any veterinary psychiatrist (yes, they exist) and they will tell you that dogs suffer from almost every psychiatric disorder that afflicts humans—all except one: schizophrenia.

If we played the quasi-philosophical game of “what defines us as human?” my first choice would be our capacity to hope and the ability to plan for the medium and distant future. But a close second is the uniquely human malady of schizophrenia.

Now, I am not being flippant. No other species is “endowed” with this psychiatric disorder. Interestingly, as I have written before, schizophrenia is associated with creative genius, a characteristic that is also uniquely human. What’s the connection, if any?

 

Genetics of schizophrenia

If you wanted to identify all the genes that are somehow associated with schizophrenia, you’d do the obvious, that is, compare the whole genome of schizophrenics with that of healthy people. I made it sound so easy, but actually, it’s quite an undertaking.

Despite the huge strides made in DNA sequencing, the accurate sequencing of a whole human genome is still far from trivial. Also, you would need to sequence thousands of individuals, both schizophrenics, and even more healthy individuals.

Why the need for massive numbers? Because the genome of every individual is, well, uniquely individual. This is because we are all continuously subject to random mutations, the vast majority of which are ‘neutral’, neither beneficial nor deleterious.

Furthermore, we all live in different environments. And as it turns out, the environment can exert its influence on our genes by inducing chemical changes, called epigenetic changes, that affect the expression of specific genes.

So, to get to the “core genome,” we have to cancel out all the “noise” in any individual genome. This can only be done by determining the sequence of thousands of genomes.

No single scientist could possibly accomplish such an undertaking. It would require the collaboration of hundreds of laboratories around the world. But, indeed this was done.

 

The Schizophrenia Working Group study

A study, published in Nature, is the result of a collaboration among more than 300 scientists from 35 countries, named the Schizophrenia Working Group of the Psychiatric Genomics Consortium. The researchers compared the whole genomes of nearly 37,000 people with schizophrenia with more than 113,000 people without the disorder. And the results?

They found 128 gene variants associated with schizophrenia, in 108 distinct locations in the human genome. The vast majority of them had never before been linked to the disorder.

Bear in mind, a study like that cannot identify specific genes that cause the disease. But, it does provide a list of genes that will become the subject of detailed investigations as to their role in the causation of the disease. But with such a long list of genes, where do you start?

 

An evolutionary approach

Why is schizophrenia uniquely human? Researchers at Mount Sinai Medical School came up with a brilliant evolutionary approach to the question.

Schizophrenia is relatively prevalent in humans despite being detrimental—the condition affects over 1% of adults. So it must be associated with something that confers a selective advantage. And that “something” must be uniquely human.

HAR human accelerated regions schizophrenia
HAR1F RF00635 rna secondary structure | by Ppgardne | via WikiCommons | CC BY-SA 3.0

Indeed, there are segments of our genome that are called human accelerated regions, or HARs. HARs are short stretches of DNA that while conserved in other species, underwent rapid evolution in humans following our split with chimpanzees, presumably since they provided some benefit specific to our species.

The genes found in those HAR stretches don’t code for proteins, instead, they regulate other genes in their vicinity. Could some schizophrenia-associated genes happen to be in the neighborhood of some HARs?

To find out, Dudley and colleagues used data culled from the Psychiatric Genomics Consortium that we mentioned above. They first assessed whether schizophrenia-related genes sit close to HARs along the human genome—closer than would be expected by chance.

It turns out they do, suggesting that HARs play a role in regulating genes contributing to schizophrenia. And, what makes those genes even more interesting is that they were found to be under stronger evolutionary selective pressure compared with other schizophrenia genes, implying that the human variants of these genes are beneficial to us in some way despite harboring schizophrenia risk.

 

Beneficial HARs

To help understand what these benefits might be, Dudley’s group then turned to gene expression profiles. Gene sequencing is important, but it can give us only their structure, not their function. So the most we could say about them is that they are associated with the disease.

To find a causal connection we need to know the function of the gene when it is turned on and off, and in what tissues. That’s what gene profiling does.

Dudley’s group found that HAR-associated schizophrenia genes are found in regions of the genome that influence other genes expressed in the prefrontal cortex (PFC). Inputs into this area arrive from the rest of the brain and are integrated to carry out higher cognitive functions that we associate with being human, such as judgment, planning, decision making, and the like.

Many of those inputs are mediated by the neurotransmitter dopamine. Others are mediated by acetylcholine, and norepinephrine, and glutamate. But all of them are excitatory. They deliver a positive signal.

Now, nothing in biology is left unchecked or unregulated. Too much of a good thing can be highly disruptive to the stability of the system. Just imagine if a whole cacophony of signals assaulted the PFC. Ideas rushing in uncensored, images flooding in unfiltered, voices unrelentingly filling our consciousness—we would go crazy.

GABA in relation to schizophrenia
Gabaergic Neurons | by Source (WP:NFCC#4) | via Wikipedia | Fair use

To prevent this dismal state of affairs, we need an inhibitory system, a yang force to counteract the yin, if you will. Thankfully, we do have such a system. There are neurons that secrete an inhibitory neurotransmitter called GABA, which tamps down the cacophony of the various signals and maintains our sanity.

So what did the gene profiling of those HAR-associated genes find? They found that they are involved in various essential human neurological functions within the PFC, including the synaptic transmission of the neurotransmitter GABA.

Not surprisingly, GABA’s impaired transmission is thought to be involved in schizophrenia. If GABA malfunctions, dopamine runs wild, contributing to the hallucinations, delusions, and disorganized thinking common to psychosis. In other words, the schizophrenic brain lacks restraint.

 

It’s all in the balance

Very few things in biology are all-or-none, like a light switch. They are more like a rheostat, dimming or brightening the light. In biology, we also refer to it as a dose-response. If you have a strong stimulus, you get an appropriately strong response.

So would it be much of a stretch if, neurobiologically speaking, creative geniuses may have a hyper-stimulated dopamine system, or alternatively, an underactive GABA system? If so, it could go a long way toward understanding their almost universal description of ideas flooding in, of visualizing sounds, of hearing conversations in their heads? And how far is that from crossing the threshold into the incapacitating pathology that we label schizophrenia?

Of course, we still don’t know for a fact that all this really happens in the brains of creative people. But one thing does seem clear, many psychiatric conditions, in addition to schizophrenia, may be related to the imbalance of signals reaching the PFC.

Paranoid ideation is closely related to schizophrenia. And, OCD, despite its frequent portrayal as a behavioral quirk, is a vicious and debilitating mental illness, with some similarities to the experiences of schizophrenia. People with OCD can have some of the same dark ideas, thoughts, and images as someone with schizophrenia, but the person with OCD is fully aware that they generate the thoughts themselves.

The studies we cited reveal how wonderfully complex the human brain is, and how exceptional the human species is. They also make it is increasingly clear, that schizophrenia and its associated psychiatric disorders, are part and parcel of us becoming what we are today. They are the price we pay for our wonderfully crafted, uniquely human brain.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

5 COMMENTS

  1. I can’t tell you if chimpanzees in the wild suffer from schizophrenia. But I haven’t seen any reoprt of schizophrenia of chimps in captivity. The reason may be because the rapid development of the prefrontal cortex happened after Homo split off from the common ancestor with chimps.

  2. A very interesting read.. Humans have the most cognitive and mental abilities..in a lay man’s term animals cannot have the creatiity ,understanding or the metal abilities such as human..so can it be concluded that’s the reason they cannot have this disease? Plus on the other side can too much of thinking, creativity lead to schizophrenia?

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