New Research Shows Schizophrenia Is a Disorder of Information Ruled by Genes

The brain is a balancing act—or, better, it's a balancing act of other balancing acts, which are themselves balancing more balancing acts and the whole big mess of chemicals and connections and electrical potentials stays just barely in line for us to step through life with a minimum of discomfort and disorder. That things routinely become horribly disordered for many millions of humans should be no surprise, but it's a slim consolation.

Schizophrenia is the mental illness characterized most explicitly by disorder. That's what it means in the most general sense: disordered thinking. The biology behind schizophrenia has been an enduring and frustrating mystery of neuroscience, but researchers at Cardiff University are releasing a study this week offering what may be the strongest evidence yet for what is going on in the brains of people with schizophrenia—a disruption of inhibitory neural signaling with genetic origins.

The result, naturally, is an imbalance, in this case between between inhibitory signaling and excitatory signaling. This is the fundamental divide in the brain: while there are loads of different sorts of synapses, they're all either one variety or the other. Inhibitory synapses (type II) look different from excitatory synapses (type I) and they're found on different parts of the neuron, which itself is receiving thousands of signals of either sort every second from an average of 7,000 different synaptic connections to other neurons.

The overall sketch looks like this. In the neuron above, the synapses located out on the cell's dendrites are excitatory, while the inhibitory synapses are located on the cell's body. The excitatory synapses receive some signal or excitation, which is passed up to a zone called the axon hillock, which is where excitatory impulses received from the dendrites are passed on to the neuron's axon, which is where the signal would be sent onwards to other neurons.

It's here that the cell has an opportunity to stop the excitatory signal. Basically, the excitation is compared against the inhibition and if it goes beyond a certain inhibitory threshold, the impulse is sent onward. Otherwise, it's effectively blocked.

What the Cardiff researchers, led by clinical neuroscientist Andrew Pocklington, found is that genetic mutations linked to schizophrenia disrupt the balance between excitation and inhibition. Specifically, they looked at what are known as copy number variants (CNVs), which are large sections of genetic code that have either been deleted en masse or duplicated. The CNVs linked to schizophrenia (e.g. statistically correlated with schizophrenia) are implicated in inhibitory disruptions, leaving the brain's balanced tipped toward excitation.

This is not a new idea. The role of overexcitation in schizophrenia (and autism) has been suggested by many different lines of evidence, including behavioral research involving mouse models and selective modifications of inhibitory and excitatory processes.

The new study bolsters all of those previous findings, but also adds new genetic evidence for the inhibitory-imbalance theory. As part of their work, the Cardiff team took 11,355 patients with schizophrenia against a control group of 16,416 people without the condition and hunted down the CNVs found in both groups and compared them, finding that the CNVs most prominent in schizophrenic patients were linked to specific brain functions.

"Our analyses support and extend previous studies… indicating a contribution to schizophrenia from complexes central to the induction and maintenance of synaptic plasticity and provide strong novel evidence for the involvement of inhibitory modulation of synaptic signalling," the authors write. "Perturbation of these processes is likely to have a widespread impact on brain function, and only a subset of genetic lesions within these systems may be compatible with a schizophrenia phenotype."

The authors call for more research on the mechanism of this disruption in oder to establish when and how it leads to schizophrenia and other conditions. "The strength of genetic evidence converging on a plausible and coherent set of biological processes provides firm foundations upon which such studies can now proceed," they wrote.

This is all less abstract than it might sound. In a very real sense, schizophrenia is a disorder of information processing. In particular, it's increasingly assumed that the disorder, or its symptoms, have to do with what's known as sensory gating. The brain is able to cope with its nonstop deluge of inputs through a process of informational prioritization, in which redundant or unnecessary stimuli are filtered out from an insurmountable flood of environmental data. If something goes wrong in this process, the result is overload: stack overflow.

A separate paper from Columbia University neurobiologists Tim Vogels and Larry Abbott explains it better: "Gating deficits, which involve difficulty in filtering external stimuli on the basis of their importance, and hallucinatory sensations, involving a failure to distinguish between real and imagined experiences, are debilitating aspects of schizophrenia. Both of these can be categorized as problems of information propagation and management."

It makes sense that the result of too much information and/or stimulation should result in disorder (a disorder of disorder). Brains don't expand reality so much as limit it, and without this function, the world can become a very, very difficult place, as nearly 51 million people worldwide can confirm.