Why Don't Animals Get Schizophrenia (and How Come We Do)?
There’s at least one mental malady that, while common in humans, seems to have spared all other animals: schizophrenia. Though psychotic animals may exist, psychosis has never been observed outside of our own species; whereas depression, OCD, and anxiety traits have been reported in many non-human species.
This begs the question of why such a potentially devastating, often lethal disease, which we now know is heavily genetic, thanks to some genomically homogenous Icelandics and plenty of other recent research, is still hanging around when it would seem that genes predisposing to psychosis would have been strongly selected against.
A new study provides clues into how the potential for schizophrenia may have arisen in the human brain and, in doing so, suggests possible treatment targets. It turns out psychosis may be an unfortunate cost of our big brains, of higher, complex cognition.
The study, led by Mount Sinai researcher Dr. Joel Dudley, proposed that since schizophrenia is relatively prevalent in humans despite being so detrimental, the condition affects over 1% of adults, that it perhaps has a complex evolutionary backstory that would explain its persistence and exclusivity to humans.
Specifically they were curious about segments of our genome 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.
Rather than encoding for proteins themselves, HARs often help regulate neighboring genes. Since both schizophrenia and HARs appear to be for the most part human-specific, the researchers wondered if there might be a connection between the two.
To find out, Dudley and colleagues used data culled from the Psychiatric Genomics Consortium, a massive study identifying genetic variants associated with schizophrenia. 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.
Furthermore, HAR-associated schizophrenia genes 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.
To help understand what these benefits might be, Dudley’s group then turned to gene expression profiles. Whereas gene sequencing provides an organism’s genome sequence, gene expression profiling reveals where and when in the body certain genes are actually active.
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, a brain region just behind the forehead involved in higher order thinking, impaired PFC function is thought to contribute to psychosis.
They also found that these culprit genes are involved in various essential human neurological functions within the PFC, including the synaptic transmission of the neurotransmitter GABA. GABA serves as an inhibitor or regulator of neuronal activity, in part by suppressing dopamine in certain parts of the brain, and it’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.